Electrophilic ring opening of oxazolines derived from serine and threonine: A practical entry to N(N)-protected β-halogeno α-aminoesters

Article abstract of DOI:10.1016/S0957-4166(98)00002-0

Treatment of oxazolines 4a-c derived from serine or threonine with chloroformates, leads to the oxazoline ring opening and to the formation of N,N-protected β-chloro-α-aminoesters la-e in 30-88% isolated yields. In the presence of NaI (0.9 equiv), oxazolines 4a,b,d react with ethyl chloroformate to afford the N,N-protected β-iodo α-amino esters 1f-h (67-89% yields), whereas the reaction of 4a,b with trimethylsilyl halide gives the analogous N-benzoyl β-halogeno derivatives 1i,k with 30-86% yields.

Full text of DOI:10.1016/S0957-4166(98)00002-0

Pergamon
Tetrahedron: Asymmetry 9 (1998) 437–447
Electrophilic ring opening of oxazolines derived from serine and
threonine: A practical entry to N(N)-protected β-halogeno
α-aminoesters
Abdelhamid Laaziri, Jacques Uziel and Sylvain Jugé ∗
Equipe ‘Réactivités spécifiques’, Université de Cergy-Pontoise, 5 mail Gay Lussac, 95031 Cergy-Pontoise Cedex, France
Received 11 November 1997; accepted 29 December 1997
Abstract
Treatment of oxazolines 4a–c derived from serine or threonine with chloroformates, leads to the oxazoline ring
opening and to the formation of N,N-protected β-chloro-α-aminoesters 1a–e in 30–88% isolated yields. In the
presence of NaI (0.9 equiv), oxazolines 4a,b,d react with ethyl chloroformate to afford the N,N-protected β-iodo
α-amino esters 1f–h (67–89% yields), whereas the reaction of 4a,b with trimethylsilyl halide gives the analogous
N-benzoyl β-halogeno derivatives 1i,k with 30–86% yields. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
2-Oxazolines are versatile heterocycles easily prepared from amino alcohols and carboxylic acids
or derivatives, which have found extensive application in organic synthesis,1 macromolecular2 and
coordination chemistry.3 These heterocycles continue to present great interest as chiral auxiliaries in
asymmetric synthesis,1b,4 and as ligands in C–C bond formation catalysis.3 In spite of the well-known
chemistry, the reaction of oxazolines with electrophilic reagents has received little attention in synthesis,
due to their polymerizability under such conditions. Nevertheless, among the electrophilic attacks1a
and besides their acidolysis5,6 or glycolysis,7 one can mention the oxazoline ring opening with acyl
chlorides,6 or chloromethyl methyl ether.8 Developing a new strategy to introduce an organophosphorus
group on the lateral chain of aminoacids, we were interested by the N(N)-protected β-halogeno alanine
derivatives 1 which are synthetic equivalents of the alanine β-anion, cation or radical (Scheme 1).9
Considerable progress has been made recently in hemisynthesis of branched α-aminoacids using zinc
reagents10 prepared from N-Boc-β-iodo alanine 1 (P=Boc, Y=H, R1=Me, X=I), and our preliminary
results indicate that compounds 1 give also useful organometallic species.11 As the preparation of these
∗
Corresponding author. Fax: 33 1 34 25 70 67; e-mail: juge@u-cergy.fr
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00002-0

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α-amino acid building blocks usually requires several steps from serine,10b,12 cystine13 or aspartic
acid,14 we report herein a simple and new method for the preparation of N,(N)-protected β-halogeno
α-aminoesters 1, by electrophilic ring opening of the oxazoline 4 with a chloroformate or a trimethylsilyl
halide.
Scheme 1.
2. Results and discussion
The oxazolines 4a–d have previously been synthesized in 80–95% yields, according to the classical
condensation15 of the appropriate iminoether hydrochlorides 3a,b, with L and D,L aminoesters 2a–c
using triethylamine as a base (Scheme 2). Treatment of the oxazolines 4a,b,d with 4 equivalents of
ethyl chloroformate, provides the N,N-protected β-chloro aminoesters 1a–c with 67–88% isolated yields
(Table 1; entries 1–3). The reaction was explained by the formation of an oxazolinium intermediate 5a,
and the nucleophilic attack of the halide ion at the C(5) position of the ring, leading to the C(5)–O(1)
bond cleavage (Scheme 2a).
Scheme 2.
When ClCO2Bn was used, the reaction with the oxazoline (ꢀ)-4b gave a mixture of N,N-protected
and N-protected β-chloro aminoesters 1d,i, which can be isolated in 30 to 60% yields (entry 4). The

A. Laaziri et al. / Tetrahedron: Asymmetry 9 (1998) 437–447
439
Table 1
Formation of N,N-protected β-halogeno α-aminoesters from reaction of oxazolines 4a–d with
ClCO2R3
formation of the minor N-benzoyl product 1i, was explained by the thermal decomposition of the
benzyl chloroformate16 and the dehydrochlorination of 1d in the conditions of the reaction, leaving
HCl responsible for the oxazoline ring opening17 (Scheme 2c). Similar results were obtained with allyl
chloroformate, since the oxazoline (ꢀ)-4b reacted to give the β-chloro alanine derivative 1e (N-Alloc,
N-benzoyl) isolated with 60% yield (entry 5). More interestingly, when the reaction between oxazolines
4a–c and ethyl chloroformate occured in the presence of 0.9 equivalent of NaI, the N,N-protected β-
iodo α-aminoesters 1f–h were obtained in 67–89% yields (75–94% with regard to NaI; entries 7–9). The
stereospecificity of the oxazoline ring opening has been controlled with 4d prepared from D,L-threonine
methyl ester 2c, giving only one diastereoisomer of the N,N-protected β-chloro erythro derivative 1c,18
after reaction with the ethyl chloroformate (Scheme 3; Table 1, entry 3). Since it is well established that
the acid solvolysis of 4d involves a ring opening with complete inversion of configuration at the C(5)
position,5a it is reasonable to assume that it is also the case here. Consequently, the formation of the pure
erythro (ꢀ)-1c proves the absence of alteration of the α-carbon configuration in this reaction.19

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A. Laaziri et al. / Tetrahedron: Asymmetry 9 (1998) 437–447
Scheme 3.
Table 2
Formation of N-benzoyl β-halogeno α-aminoesters from reaction of oxazolines 4a,b with TMSX
Since the reaction of ethyl chloroformate in the presence of NaBr proceeds with a poor efficiency
(Table 1; entry 6), the ring opening of oxazolines 4a,b has been performed with a trimethylsilyl halide as
the electrophilic reagent (Scheme 2b, Table 2).
Thus, treatment of (ꢀ)-4b with trimethyl silyl chloride in refluxing THF led to the N-benzoyl β-
chloro-α-aminoester 1i with 86% yield (Table 2, entry 1). In similar conditions, the reaction of oxazoline
(+)-4b with TMSBr afforded the β-bromo derivative 1j with 57% yield, whereas in CH2Cl2 the yield
increased to 85% (Table 2, entries 2 and 3). Finally, when TMSI reacted with the oxazoline (ꢀ)-4a, the
N-benzoyl β-iodo-α-amino ester 1k was isolated with a moderate yield of 30% (Table 2, entry 4). As in
the case of chloroformates, we think that this reaction occurs via the formation of the N-trimethylsilyl
oxazolinium salt 5b (Scheme 2b), leading to the N-benzoyl β-halogeno products 1i–k after hydrolysis of
the N-trimethylsilyl-N-benzoyl intermediates 1l–n (X=Cl, Br, I).
In summary, we have found a new and convenient method for the preparation of N,N-protected β-
chloro-α-aminoesters 1a–e in 30–88% overall yields, without alteration of the α-carbon configuration,
and by reaction of chloroformates with oxazolines 4a,b,d prepared from serine or threonine. It is
noteworthy that in the presence of NaI, the N,N-protected β-iodo aminoesters 1f–h were obtained in
high yields (67–89%), whereas it was preferable to use TMSBr to obtain cleanly the analogous β-bromo
alanine derivative 1j (85% yield). The methodology described here, furnishes a general approach for the
synthesis of enantiomerically pure β-halogeno α-aminoesters 1, by simply changing the electrophilic
reagent in the reaction with the oxazoline 4. Finally, oxazolines derived from β-hydroxy α-aminoesters
are promising chiral synthons for branched amino acids synthesis.

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441
3. Experimental section
3.1. General
All reactions were carried out under an argon atmosphere in glassware dried overnight. Solvents
were dried and freshly distilled under an argon atmosphere over sodium/benzophenone for THF and
ether, and over CaH2 for toluene, CH2Cl2 and CHCl3. L and DL-serine, DL-threonine and trimethylsilyl
bromide were purchased from Aldrich. Trimethylsilyl iodide, allyl, benzyl, ethyl chloroformates and
pivalonitrile were purchased from Acros Organics. Trimethylsilylchloride was purchased from Lancaster.
The phenyl and tert-butyl imino ethyl ether hydrochlorides 3a and 3b were obtained by bubbling HCl
gas in a solution of the corresponding nitrile with ethanol.4e,21 The serine and threonine esters 2a–c
were prepared from the reaction of acetyl chloride with the corresponding amino acid, in solution in
methanol or ethanol.15 Sodium iodide was dried by heating at 140°C under reduced pressure for 8 h in the
dark. Flash chromatography was realized on silica gel (230–400 mesh; Merck) and when necessary pure
samples were obtained by preparative TLC on commercially tapered silica gel plates 60F254+366(Merck).
All NMR spectra data were obtained on Bruker DPX 250 and AM 400 spectrometers using TMS as
an internal reference. Infrared spectra were recorded on a Perkin–Elmer 1600 FT spectrometer. Melting
points were mesured on a Büchi melting point apparatus and are uncorrected. Optical rotations values
were determined at 20°C on a Perkin–Elmer 241 polarimeter. Mass spectral analyses were performed on
a NERMAG R10-10C and a KRATOS MS-50 for exact mass, at the Mass Spectroscopy Laboratories of
ENSCP and the Structural Chemistry Laboratories of P. & M. Curie University (Paris). The major peak
m/z is mentioned with the intensity as a percentage of the base peak in brackets. Elemental analyses were
mesured with a precision superior to 0.3% at the Microanalysis Laboratories of P. & M. Curie University
(Paris), and at the CNRS (Vernaison, France).
3.2. Typical procedure for oxazolines15
A 250 mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged
with derivative 2 (22.5 mmol), 100 mL of chloroform, imino ethyl ether hydrochloride 3 (22.5 mmol)
and 2.27 g of triethylamine (22.5 mmol). The mixture was refluxed for 30 h. The solvent was removed
and the residue purified by chromatography on silica gel with cyclohexane:AcOEt (1:1) as the eluent to
give compound 4.
3.3. 2-Phenyl-4-carbomethoxy-2-oxazoline 4a4e,15
Yield=80%; colourless oil; Rf=0.35 (cyclohexane:AcOEt=1:1); IR (neat, ν cm−1): 2953 (m), 1742
1
3
(vs), 1644 (s), 1214 (vs), 1088 (s); H NMR (CDCl3): δ 7.99 (2H, d, J=7.9, H arom), 7.43–7.33 (3H,
3
3
2
m, H arom), 4.88 (1H, dd, J=7.8, J=10.5, CHN), 4.65 (1H, t, J=8.6, C(H)H), 4.52 (1H, dd, J=8.7,
3J=10.6, CH(H)), 3.76 (3H, s, CO2CH3); 13C NMR (CDCl3): δ 171.6 (CO2Me), 166.1 (CN), 131.8
(CH arom), 128.6 (CH arom), 128.3 (CH arom), 127.0 (C arom), 69.6 (CHCH2O), 68.6 (CHN), 52.6
(CO2CH3).
3.4. (S)-(+)-2-Phenyl-4-carboethoxy-2-oxazoline 4b22
Yield=95%; crystals, mp<40°C; [α]D20=+90.9 (c=0.2, CHCl3); Rf=0.38 (cyclohexane:AcOEt=1:1);
IR (neat, ν cm−1): 2981 (m), 1736 (s), 1641 (s), 1194 (vs), 1089 (s); 1H NMR (CDCl3): δ 8.0 (2H, dd,

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A. Laaziri et al. / Tetrahedron: Asymmetry 9 (1998) 437–447
3
3
3
3J=7, J=8.5, H arom), 7.48–7.36 (3H, m, H arom), 4.91 (1H, dd, J=7.9, J=10.6, CHN), 4.67 (1H, t,
2
3
3
J=8.4, OC(H)H), 4.56 (1H, dd, J=8.8, J=10.6, OCH(H)), 4.26 (2H, dq, J=7.2, CO2CH2CH3), 1.31
(3H, t, 3J=7.1, CO2CH2CH3); 13C NMR (CDCl3): δ 171.2 (CO2Et), 166.2 (CN), 132.2 (CH arom), 128.9
(CH arom), 128.7 (CH arom), 126.4 (C arom), 70.0 (CHCH2O), 69.1 (CHN), 62.1 (CO2CH2CH3), 14.5
(CO2CH2CH3). Anal. calcd for C12H13NO3 (219): C 65.74, H 5.97, N 6.39; found: C 65.64, H 5.95, N
6.36.
3.5. (S)-(+)-2-tert-Butyl-4-carboethoxy-2-oxazoline 4c
Yield=80%; colourless oil; [α]D20=+36.6 (c=2.1, CHCl3); Rf=0.4 (cyclohexane:AcOEt=1:1); IR (neat,
1
ν cm−1): 2977 (vs), 1740 (s), 1651 (s), 1194 (vs), 1146 (s); H NMR (CDCl3): δ 4.68 (1H, dd,
3
3
3J=7.5, J=10.5, CHN), 4.40 (2H, 2dd, CHCH2O), 4.22 (2H, dq, J=7, CO2CH2CH3), 1.30 (3H, t,
3J=7, CO2CH2CH3), 1.24 (9H, s, C(CH3)3); 13C NMR (CDCl3): δ 176.9 (CN), 171.5 (CO2Et), 69.6
(CHCH2O), 68.3 (CHN), 61.4 (CO2CH2CH3), 33.4 (C(CH3)3), 27.6 (C(CH3)3), 14.1 (CO2CH2CH3).
Anal. calcd for C10H17NO3 (199): C 60.30, H 8.54, N 7.04; found: C 60.24, H 8.48, N 7.03.
3.6. (ꢀ)-2-Phenyl-5-methyl-4-carbomethoxy-2-oxazoline 4d4b
Yield=80%; colourless oil; Rf=0.52 (CHCl3:Et2O=7:3); IR (neat, ν cm−1): 2953 (m), 1742 (s), 1642
1
(s), 1203 (vs); H NMR (CDCl3): δ 8.1–8 (2H, m, H arom), 7.6–7.3 (3H, m, H arom), 5.0 (1H, m,
CHO), 4.45 (1H, d, 3J=8, CHN), 3.8 (3H, s, CO2CH3), 1.5 (3H, d, 3J=7, CH3CH). HRMS (EI) calcd for
C12H13NO3 [M] 219.0895; found 219.0896.
3.7. (R)-(−)-Methyl [2-(N-benzoyl-N-ethoxycarbonyl) amino-3-chloro] propanoate 1a
A 100 mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged
with 3 g of oxazoline (+)-4a (14.6 mmol), 9 mL of ethyl chloroformate (94.5 mmol) and 40 mL of THF.
The mixture was refluxed for 36 h. The solvent was removed and the residue purified by chromatography
on silica gel with cyclohexane:AcOEt (4:1) as the eluent to give 3.91 g of compound 1a (85% yield).
Colourless oil; [α]D20=−40.7 (c=2.6, CHCl3); Rf=0.73 (cyclohexane:AcOEt=1:1); IR (neat, ν cm−1):
1
2955 (m), 1746 (s), 1682 (s), 1258 (s), 1069 (m), 1017 (s); H NMR (CDCl3): δ 7.65–7.38 (5H, m, H
3
3
arom), 5.41 (1H, t, J=7.6, CHN), 4.23 (2H, d, J=7.6, CH2Cl), 4.01 (2H, q, 3J=7.1, NCO2CH2CH3),
3.77 (3H, s, CO2CH3), 0.87 (3H, t, 3J=7.1, NCO2CH2CH3); 13C NMR (CDCl3): δ 172.5 (PhCO), 168.2
(CO2Me), 154.3 (NCO2Et), 136.4 (C arom), 131.7 (CH arom), 128.2 (CH arom), 127.9 (CH arom),
63.4 (NCO2CH2CH3), 59.3 (CHN), 52.9 (CO2CH3), 42.2 (CH2Cl), 13.4 (NCO2CH2CH3); MS (EI) m/z
(relative intensity): 313 (M+; 6), 278 (M−Cl+; 31), 254 (14), 240 (10), 218 (11), 189 (17), 105 (100),
77 (100). Anal. calcd for C14H16ClNO5 (313.5): C 53.60, H 5.14, N 4.46, O 25.49, Cl 11.30; found: C
53.88, H 5.32, N 4.79, O 25.24, Cl 10.97.
3.8. (R)-(−)-Ethyl [2-(N-benzoyl-N-ethoxycarbonyl) amino-3-chloro] propanoate 1b
A 100 mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged
with 1.5 g of oxazoline (+)-4b (6.8 mmol), 2.6 mL of ethyl chloroformate (27.2 mmol) and 20 mL of THF.
The mixture was refluxed for 36 h. The solvent was removed and the residue purified by chromatography
on silica gel with cyclohexane:AcOEt (4:1) as the eluent to give 1.98 g of compound 1b (88% yield).
Colourless oil; [α]D20=−35.3 (c=2.2, CHCl3); Rf=0.55 (cyclohexane:AcOEt=1:1); IR (neat, ν cm−1):

A. Laaziri et al. / Tetrahedron: Asymmetry 9 (1998) 437–447
443
1
2983 (m), 1742 (s), 1686 (s), 1263 (s), 1022 (s); H NMR (CDCl3): δ 7.70–7.36 (5H, m, H arom),
3
3
3
5.40 (1H, dd, J=6.3, J=6.5, CHN), 4.28–4.22 (4H, m, CH2Cl, CO2CH2CH3), 4.01 (2H, q, J=7.3,
NCO2CH2CH3), 1.27 (3H, t, J=6.8, CO2CH2CH3), 0.86 (3H, t, J=7.3, NCO2CH2CH3); 13C NMR
(CDCl3): δ 171.3 (PhCO), 166.4 (CO2Et), 153.0 (NCO2Et), 135.2 (C arom), 130.4 (CH arom), 127.2
(CH arom), 126.2 (CH arom), 62.4 (NCO2CH2CH3), 60.9 (CO2CH2CH3), 58.4 (CHN), 41.1 (CH2Cl),
12.8 (NCO2CH2CH3), 12.1 (CO2CH2CH3). Anal. calcd for C15H18ClNO5 (327.5): C 54.97, H 5.53, N
4.27; found: C 54.48, H 5.69, N 4.13.
3
3
3.9. (ꢀ)-Methyl erythro [2-(N-benzoyl-N-ethoxycarbonyl) amino-3-chloro] butanoate 1c
A 100 mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged
with 2 g of oxazoline (ꢀ)-4c (8.6 mmol), 3 mL of ethyl chloroformate (31.4 mmol) and 30 mL of THF.
The mixture was refluxed for 30 h. The solvent was removed and the residue purified by chromatography
on silica gel to give 2.18 g of compound 1c (67% yield). Colourless oil; Rf=0.66 (CH2Cl2); IR (neat,
3
ν cm−1): 2934 (m), 1742 (s), 1687 (s), 1227 (vs), 1033 (m). 1H NMR (CDCl3): δ 7.61 (2H, d, J=7.6,
3
3
3
H arom), 7.53 (1H, t, J=7.4, H arom), 7.42 (2H, t, J=7.6, H arom), 5.32 (1H, d, J=7.4, CHN), 4.84
(1H, p, 3J=6.8, CHCl), 4.02 (2H, q, 3J=7.1, NCO2CH2CH3), 3.79 (3H, s, CO2CH3), 1.58 (3H, d, 3J=6.7,
CH3CHCl), 0.89 (3H, t, 3J=7.2, NCO2CH2CH3); 13C NMR (CDCl3): δ 172.4 (PhCO), 168.3 (CO2CH3),
154.4 (NCO2Et), 136.0 (C arom), 131.9 (CH arom), 128.3 (CH arom), 127.8 (CH arom), 63.7 (CHN),
63.4 (NCO2CH2CH3), 54.6 (CHCl), 52.7 (CO2CH3), 21.6 (CH3CHCl), 13.4 (NCO2CH2CH3); MS (EI)
m/z (relative intensity): 292 (M+−Cl; 3); 232 (4); 105 (100); 85 (12); 83 (18); 77 (20); Anal. calcd for
C15H18ClNO5 (327.5): C 54.97, H 5.53, N 4.27, O 24.41; found: C 54.53, H 5.99, N 3.73, O 24.87.
3.10. (ꢀ)-Ethyl [2-(N-benzoyl-N-benzyloxycarbonyl) amino-3-chloro] propanoate 1d
A 10 mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged
with 0.1 g of oxazoline (ꢀ)-4b (0.5 mmol), 0.28 mL of benzyl chloroformate (2 mmol) and 3 mL of THF.
The mixture was refluxed for 24 h. The solvent was removed and the residue purified by chromatography
on silica gel with cyclohexane:AcOEt (1:1) as the eluent to give 0.12 g of compound 1d (60% yield).
Colourless oil; Rf=0.63 (CH2Cl2); IR (neat, ν cm−1): 3064 (m), 2982 (m), 1739 (vs), 1682 (s), 1449 (s),
1265 (vs), 1220 (s), 1164 (s), 1020 (s); 1H NMR (CDCl3): δ 7.63 (2H, d, 3J=7.2, CH arom), 7.46–7.42
4
(1H, m, CH arom), 7.34–7.26 (2H, m, H arom), 7.23–7.18 (3H, m, H arom), 6.88 (2H, dd, J=1.3,
3
3J=7.2, CH arom), 5.41 (1H, dd, J=6.4, 9.1, CHN), 4.98 (2H, s, CH2Ph), 4.30–4.22 (2H, m, CH2Cl),
3
3
4.14 (2H, dq, J=7.1, CO2CH2CH3), 1.16 (3H, t, J=7.1, CO2CH2CH3); 13C NMR (CDCl3): δ 172.3
(PhCO), 167.5 (CO2Et), 154.2 (NCO2Bn), 136.0 (C arom), 133.9 (C arom), 131.8 (CH arom), 128.5 (CH
arom), 128.4 (CH arom), 128.3 (CH arom), 128.0 (CH arom), 69.6 (OCH2Ph), 62.6 (CO2CH2CH3), 60.0
(CHN), 42.7 (CH2Cl), 14.4 (CO2CH2CH3). HRMS (EI) calcd for C20H20ClNO5 [M] 389.1030; found
389.1030.
3.11. (ꢀ)-Ethyl [2-(N-allyloxycarbonyl-N-benzoyl) amino-3-chloro] propanoate 1e
A 10 mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged
with 0.22 g of oxazoline (ꢀ)-4b (1 mmol), 0.5 mL of allyl chloroformate (4.7 mmol) and 3 mL of THF.
The mixture was refluxed for 20 h. The solvent was removed and the residue purified by chromatography
on silica gel with cyclohexane:AcOEt (1:1) as the eluent to give 0.21 g of compound 1e (60% yield).
Colourless oil; Rf=0.60 (cyclohexane:AcOEt=1:1); IR (neat, ν cm−1): 2984 (m), 1746 (s), 1682 (s),

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1
3
1381 (s), 1337 (s), 1260 (s), 1221 (s), 1170 (s), 1020 (s); H NMR (CDCl3): δ 7.67 (2H, d, J=7.1, H
arom), 7.53–7.39 (3H, m, H arom), 5.53–5.45 (1H, m, CH=C), 5.42 (1H, t, 3J=8.2, CHN), 5.07 (1H, dd,
4J=1.1, 2J=10.3, CH(Hcis)_CH), 5.02 (1H, dd, 4J=1.2, 3J=17.6, CH(Htrans)_CH), 4.45 (2H, dd, 4J=1.2,
3
3J=5.9, CH2CH_C), 4.29–4.19 (4H, m, CH2Cl, CO2CH2CH3), 1.26 (3H, t, J=7.3, CO2CH2CH3);
13C NMR (CDCl3): δ 172.4 (PhCO), 167.6 (CO2Et), 154.1 (NCO2All), 136.1 (C arom), 131.88 (CH
arom), 130.4 (CH_CH2), 128.3 (CH arom), 128.0 (CH arom), 119.1 (CH_CH2), 67.8 (NCO2CH2), 62.2
(CO2CH2CH3), 59.5 (CHN), 42.2 (CH2Cl), 14.1 (CO2CH2CH3). HRMS (EI) calcd for C16H18ClNO5
[M] 339.0873; found 339.0872.
3.12. (ꢀ)-Methyl [2-(N-benzoyl-N-ethoxycarbonyl) amino-3-iodo] propanoate 1f
A 100 mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged
with 3 g of oxazoline (ꢀ)-4a (14.63 mmol), 5.6 mL of freshly distilled ethyl chloroformate (58.52 mmol)
and 50 mL of dichloromethane. Then 2 g of anhydrous NaI (13.1 mmol) was added and the mixture was
refluxed for 24 h in the dark. The solution was cooled, the salt filtered and the filtrate evaporated. The
residue was purified by chromatography on silica gel with dichloromethane as the eluent to give 5.03 g of
compound 1f (85% yield). Yellow oil; Rf=0.30 (cyclohexane:AcOEt=1:1); IR (neat, ν cm−1): 2984 (m),
2953 (m), 1744 (vs), 1681 (s), 1263 (s), 1156 (m), 1057 (m); 1H NMR (CDCl3): δ 7.72 (2H, dd, 4J=1.5,
3J=8.5, H arom), 7.51–7.39 (3H, m, H arom), 5.36 (1H, dd, 3J=5.7, 3J=10.1, CHN), 4.03 (2H, q, 3J=7.1,
3
CO2CH2CH3), 3.94–3.90 (2H, m, CH2I), 3.78 (3H, s, CO2CH3), 0.89 (3H, t, J=7.1, NCO2CH2CH3);
13C NMR (CDCl3): δ 172.9 (PhCO), 168.5 (CO2CH3), 154.8 (NCO2CH2CH3), 136.9 (C arom), 132.4
(CH arom), 129.1 (CH arom), 128.8 (CH arom), 64.1 (NCO2CH2CH3), 60.2 (CHN), 53.7 (CO2CH3),
14.0 (NCO2CH2CH3), 2.4 (CH2I). Anal. calcd for C14H16INO5 (4O5): C 41.50, H 3.98, N 3.46; found:
C 41.64, H 4.01, N 3.47.
3.13. (R)-(−)-Ethyl [2-(N-benzoyl-N-ethoxycarbonyl) amino-3-iodo] propanoate 1g
A 100 mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged
with 3.2 g of oxazoline (+)-4b (14.63 mmol), 5.6 mL of freshly distilled ethyl chloroformate (58.52
mmol) and 50 mL of dichloromethane. Then 2 g of anhydrous NaI (13.71 mmol) was added and the
mixture was refluxed for 24 h in the dark. The solution was cooled, the salt filtered and the filtrate
evaporated. The residue was purified by chromatography on silica gel with dichloromethane as the
eluent to give 4.8 g of compound 1h (78% yield). Yellow oil; [α]D20=−20.6 (c=1.2, CHCl3); Rf=0.59
(CH2Cl2); IR (neat, ν cm−1): 2983 (m), 1739 (vs), 1681 (vs), 1254 (vs), 1156 (s), 1110 (m), 1056 (s),
1019 (s); 1H NMR (CDCl3): δ 7.72 (2H, dd, 4J=1.8, 3J=7.9, H arom), 7.51–7.41 (3H, m, H arom), 5.35
(1H, dd, 3J=6.1, 3J=9.7, CHN), 4.27–4.20 (2H, m, CO2CH2CH3), 4.02 (2H, q, 3J=7.1, NCO2CH2CH3),
3
3
3.97–3.86 (2H, m, CH2I), 1.27 (3H, t, J=7.1, CO2CH2CH3), 0.89 (3H, t, J=7.1, NCO2CH2CH3);
13C NMR (CDCl3): δ 172.6 (PhCO), 167.7 (CO2Et), 154.6 (NCO2Et), 136.8 (C arom), 132.0 (CH
arom), 128.8 (CH arom), 128.5 (CH arom), 63.8 (NCO2CH2CH3), 62.6 (CO2CH2CH3), 60.1 (CHN),
14.4 (NCO2CH2CH3), 13.7 (CO2CH2CH3), 2.4 (CH2I); MS (EI) m/z: 420 (M+1), 374 (M−OEt), 292
(M−I), 105 (PhCO); Anal. calcd for C15H18INO5 (419): C 42.98, H 4.32, N 3.34; found: C 43.15, H
4.32, N 3.30.

A. Laaziri et al. / Tetrahedron: Asymmetry 9 (1998) 437–447
445
3.14. (R)-(−)-Ethyl [2-(N-ethoxycarbonyl-N-tert-butylcarbonyl) amino-3-iodo] propanoate 1h
A 25 mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged
with 1.2 g of oxazoline (+)-4d (6.06 mmol), 2.3 mL of freshly distilled ethyl chloroformate (24 mmol)
and 50 mL of dichloromethane. Then 0.83 g of anhydrous NaI (5.54 mmol) was added and the mixture
was refluxed for 48 h in the dark. The solution was cooled, the salt filtered and the filtrate evaporated.
The residue was purified by chromatography on silica gel with dichloromethane as the eluent to give
1.64 g of compound 1h (75% yield). Yellow oil; [α]D20=−3.9 (c=1.4, CHCl3); Rf=0.59 (CH2Cl2);
IR (neat, ν cm−1): 2981 (s), 1739 (vs), 1693 (s), 1483 (m), 1465 (m), 1259 (s), 1178 (s), 1153
1
3
3
(s), 1064 (m), 1021 (m); H NMR (CDCl3): δ 4.98 (1H, dd, J=4.4, J=11.0, CHN), 4.29 (2H, q,
3J=7.1, CO2CH2CH3), 4.16 (2H, qd, J=2.6, J=7.2, NCO2CH2CH3), 3.85 (1H, dd, J=4.4, J=10.9,
3
2
3
C(H)H), 3.62 (1H, t, J=11.0, CH(H)), 1.38 (9H, s, C(CH3)3), 1.35 (3H, t, J=7.2, CO2CH2CH3),
1.25 (3H, t, J=7.1, NCO2CH2CH3); 13C NMR (CDCl3): δ 185.0 (t-BuCO), 167.7 (CO2Et), 154.4
3
(NCO2Et), 63.4 (NCO2CH2CH3), 62.1 (CO2CH2CH3), 61.4 (CHN), 43.8 (C(CH3)3), 28.3 (C(CH3)3),
14.1 (NCO2CH2CH3), 14.0 (CO2CH2CH3), 2.1 (CH2I); MS (CI, NH3) m/z: 399 (M+), 272 (M+−I), 200
(M+−I−CO2Et), 85 (t-BuCO+).
3.15. (ꢀ)-Ethyl [2-(N-benzoyl)amino-3-chloro] propanoate 1i 13b,23
A 25 mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged
with 0.23 g of oxazoline (ꢀ)-4b (1 mmol), 0.5 mL of trimethylsilyl chloride (4 mmol) and 3 mL of
THF. The mixture was refluxed for 8 h and was hydrolyzed at room temperature. The solution was
extracted with dichloromethane and dried over magnesium sulfate. The solvent was removed and the
residue purified by chromatography on silica gel with dichloromethane as the eluent to give 0.22 g
of compound 1i (86% yield). White solid; mp=94°C; Rf=0.45 (cyclohexane:AcOEt=1:1); IR (KBr, ν
1
3
cm−1): 3322 (s), 1744 (s), 1639 (s), 1222 (s), 1040 (m); H NMR (CDCl3): δ 7.83 (2H, d, J=7, H
3
arom), 7.51–7.40 (3H, m, H arom), 7.21 (1H, d, J=7, NH), 5.17–5.11 (1H, m, CHN), 4.33–4.24 (2H,
m, CO2CH2CH3), 4.05–4.03 (2H, m, CH2Cl), 1.30 (3H, t, 3J=7.1, CO2CH2CH3); 13C NMR (CDCl3): δ
168.9 (PhCO), 167.1 (CO2Et), 133.5 (C arom), 132.0 (CH arom), 128.6 (CH arom), 127.2 (CH arom),
62.4 (CO2CH2CH3), 53.7 (CHN), 45.2 (CH2Cl), 14.1 (CO2CH2CH3).
3.16. (R)-(+)-Ethyl [2-(N-benzoyl)amino-3-bromo] propanoate 1j
A 50 mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged
with 2 g of oxazoline (+)-4b (9.13 mmol), 2 mL of trimethylsilyl bromide (15.2 mmol) and 30 mL
of dichloromethane. The mixture was refluxed for 48 h and was hydrolyzed at room temperature. The
solution was extracted with dichloromethane and dried over magnesium sulfate. The solvent was removed
and the residue purified by chromatography on silica gel with dichloromethane as the eluent to give
2.33 g of compound 1j (85% yield). White solid; mp=107°C; [α]D20=+45.9 (c=2.2, CHCl3); Rf=0.38
(cyclohexane:AcOEt=1:1); IR (KBr, ν cm−1): 3299 (s), 2981 (w), 1733 (s), 1687 (s), 1327 (m), 1234
1
3
(m), 1151 (m), 1036 (m); H NMR (CDCl3): δ 7.84 (2H, d, J=6.9, H arom), 7.60–7.40 (3H, m, H
3
3
arom), 7.48 (1H, d, J=6.5, NH), 5.22–5.16 (1H, m, CHN), 4.28 (2H, q, J=7.2, CO2CH2CH3), 3.91
(2H, d, 3J=3.4, CH2Br), 1.37 (3H, t, 3J=7.2, CO2CH2CH3); 13C NMR (CDCl3): δ 169.0 (PhCO), 167.0
(CO2Et), 133.5 (C arom), 132.0 (CH arom), 128.8 (CH arom), 127.2 (CH arom), 62.4 (CO2CH2CH3),
53.1 (CHN), 33.7 (CH2Br), 14.2 (CO2CH2CH3); MS (EI) m/z (relative intensity): 301 (M++2; 1), 299

446
A. Laaziri et al. / Tetrahedron: Asymmetry 9 (1998) 437–447
(M+; 1), 219 (8), 146 (17), 105 (100), 77 (38), 51 (10). Anal. calcd for C12H14BrNO3 (300): C 48.16, H
4.70, N 4.67; found: C 48.37, H 4.96, N 4.61.
3.17. (ꢀ)-Methyl [2-(N-benzoyl)amino-3-iodo] propanoate 1k
According to the same procedure as for compound 1i, replacing TMSCl by TMSI, 0.1 g of 1k was
obtained (30% yield). Uncrystallized; Rf=0.48 (CH2Cl2); IR (KBr, ν cm−1): 3294 (s), 2951 (w), 1735
(s), 1643 (s), 1224 (s), 1146 (s); 1H NMR (CDCl3): δ 7.85 (2H, d, 3J=6.7, H arom), 7.56–7.48 (3H, m, H
arom), 6.95 (1H, d, 3J=7, NH), 4.99 (1H, td, 3J=7, 3J=3.6, CHN), 3.86 (3H, s, CO2CH3), 3.74 (2H, 2dd,
3
2J=10.4, J=3.6, CH2I); 13C NMR (CDCl3): δ 169.7 (PhCO), 167.1 (CO2Me), 133.0 (C arom), 132.0
(CH arom), 128.6 (CH arom), 127.2 (CH arom), 53.1 (CHN), 52.6 (CO2CH3), 7.1 (CH2I). Anal. calcd
for C11H12INO3 (333): C 39.64, H 3.60, N 4.20; found: C 39.72, H 3.66, N 4.14.
Acknowledgements
We thank Mrs. G. Dosseh for her help in NMR analysis, Mr. F. Meyer for his partial contribution and
the Ministry of Research for financial support to our team.
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