Stereoselective synthesis of fluorinated β-aminoacids from ethyl trans- N-benzyl-3-trifluoromethylaziridine-2-carboxylate

Article abstract of DOI:10.1016/S0957-4166(99)00246-3

trans-N-Benzyl-3-trifluoromethyl-2-ethoxycarbonylaziridine 2a, easily obtainable in enantiopure forms by CAL-catalysed enzymatic resolution, allowed the regio- and stereoselective synthesis of chiral fluorinated anti- α-functionalised-β-aminoacids, such as trifluoroisoserinates or trifluoro- β-alanine, and trans-3-halo- or 3-hydroxy-β-lactams. Starting from the enantiomerically pure methyl analogue of the title compound, 2c, pure enantiomers of trifluoroisoserine can be obtained in high overall chemical yield. Absolute configurations of optically active β-aminoacids were determined by chemical correlation.

Full text of DOI:10.1016/S0957-4166(99)00246-3

Pergamon
Tetrahedron: Asymmetry 10 (1999) 2361–2371
Stereoselective synthesis of fluorinated β-aminoacids from ethyl
trans-N-benzyl-3-trifluoromethylaziridine-2-carboxylate
Paolo Davoli, Arrigo Forni, Chiara Franciosi, Irene Moretti and Fabio Prati ∗
Dipartimento di Chimica, Università di Modena e Reggio Emilia, Via Campi 183, 41100 Modena, Italy
Received 17 May 1999; accepted 15 June 1999
Abstract
trans-N-Benzyl-3-trifluoromethyl-2-ethoxycarbonylaziridine 2a, easily obtainable in enantiopure forms by
CAL-catalysed enzymatic resolution, allowed the regio- and stereoselective synthesis of chiral fluorinated anti-α-
functionalised-β-aminoacids, such as trifluoroisoserinates or trifluoro-β-alanine, and trans-3-halo- or 3-hydroxy-
β-lactams. Starting from the enantiomerically pure methyl analogue of the title compound, 2c, pure enantiomers
of trifluoroisoserine can be obtained in high overall chemical yield. Absolute configurations of optically active
β-aminoacids were determined by chemical correlation. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
β-Aminoacids and their derivatives, such as α-hydroxy- or α-halocompounds, are the object of
constant interest as intermediates in the synthesis of β-lactams, of Taxol® semisynthetic analogues and
as peptidomimetic units.1 In the last few years a great deal of research has been devoted to the synthesis
of fluorinated analogues of non-proteinogenic β-aminoacids as highly biologically active molecules with
a wide range of potential applications.1b,2 Among these, the main source of fluorinated isoserinates and
isoserines is the ring opening hydrolysis of the corresponding β-lactams;1c,2b these compounds, in the
syn diastereoisomeric form, were coupled with baccatins for the synthesis of new taxoids. Nevertheless,
relatively few methods for the synthesis of enantiomerically pure β-aminoacids are available: many
of the procedures are known to be complicated, and by contrast with the derivatives of natural α-
aminoacids, functionalised β-aminoacids are difficult to obtain in enantiomerically pure form, and often
only by complex procedures.1,2 As a consequence, new approaches to stereoselective and enantioselective
synthetic methods could be of interest.
Aziridine-2-carboxylates are known to be versatile key intermediates for the synthesis of α- and β-
aminoacids: the ring strain makes these compounds reactive towards a wide range of nucleophiles, often
∗
Corresponding author. E-mail: prati.fabio@unimo.i
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00246-3

2362
P. Davoli et al. / Tetrahedron: Asymmetry 10 (1999) 2361–2371
in regio- and stereoselective ways.3 Either α- or β-aminoacids can be obtained by nucleophilic attack
at the C-3 or the C-2 aziridine ring carbon atom, respectively.4 Nevertheless, the stereoselective ring
opening at C-2 is reported to be relatively rare: recently, the regiospecific C-2 nucleophilic ring opening of
aziridine-2-carboxylates to β-aminoacids was achieved only after their conversion into the corresponding
aziridino alcohols.5
Here we report the regio- and stereoselective nucleophilic ring opening of trans-1-benzyl-3-
trifluoromethyl-2-ethoxycarbonylaziridines 2a,c,d, allowing the regio- and stereocontrolled synthesis of
chiral β-aminoacids, such as anti-α-halo-β-trifluoromethyl-β-alanine 3a,b, β-trifluoromethyl-β-alanine
3c, anti-3-(trifluoromethyl)isoserinates 3d–h, as well as the synthesis of fluorinated trans-β-lactams
4a,b.
anti-α-Hydroxy-β-aminoacids are known to convert into the corresponding syn derivatives, required
by the natural products, under Mitsunobu conditions.6 Moreover, 3-halo-β-lactam might be a possible
precursor of β-lactamase inibitors7 and a potentially useful intermediate for the synthesis of fluorinated
analogues of aztreonam, 3-amino-4-trifluoromethyl-β-lactam.8
2. Results and discussion
2.1. trans-1-Benzyl-3-trifluoromethyl-2-ethoxycarbonylaziridine 2a: synthesis and enzymatic resolution
Aziridine trans-2a was synthesised in high overall yield (90%) following the procedure described
elsewhere,9 by reaction with benzylamine from ethyl 2,3-dibromo-4,4,4-trifluorobutanoate 1, obtained
by bromination of the commercially available ethyl trans-4,4,4-trifluoro-2-butenoate. By hydrogenation
of 2a in the presence of Pd–C (10%), the corresponding 1H-aziridine 2d was obtained in 87% yield.9
Racemic aziridine 2a was resolved by enzymatic hydrolysis, catalysed by Candida antarctica lipase
(CAL): the ester function was hydrolysed with high enantioselectivity, as expressed by the enantiomeric
ratio E >100.10 The resolution of 2a was carried out in phosphate buffer (0.1 mol dm−3 and NaCl 0.1 mol
dm−3; pH 7.5), at 37°C and with an enzyme/aziridine ratio (w/w) 1:50. The suspension was vigorously
shaken and the reaction stopped after 30 min, when conversion reached 45%: under these conditions,
the optically active unchanged ester (+)-2a, (ee 83%), was isolated from the reaction mixture in 54%
chemical yield, by extraction with diethyl ether followed by column chromatography. The optically
active hydrolysis product, aziridinecarboxylic acid (−)-2b, was recovered from the aqueous phase by
acidification with HCl 10% until pH 1 and extraction with ethyl acetate (35% yield). The enantiomeric
excess of (−)-2b (ee >98%) was estimated after its conversion into the corresponding methyl ester (−)-2c,
by treatment with diazomethane (Scheme 1). Enantiomeric excesses (ees) were evaluated on a chiral B-

P. Davoli et al. / Tetrahedron: Asymmetry 10 (1999) 2361–2371
2363
DEX 120 column. The conversion and E were determined from the values of the enantiomeric excesses
of the unhydrolysed (ees) and hydrolysed (eep) products.10
Scheme 1.
2.2. Nucleophilic ring-opening reactions
The ring-opening reactions, to afford non-natural β-aminoacids 3a–h, were performed on racemic
aziridines 2a,d by treatment with Brønsted acids, such as HCl, MgBr2 in H2SO4 or trifluoroacetic
acid. In particular, trifluoroacetolysis was performed on (+)-2a (ee 83%) and (−)-2c (ee >98%) to
obtain trifluoromethylisoserinates in both enantiomeric forms. Moreover, the ring-opening product (+)-
3b, obtained by treatment of (+)-2a with MgBr2 in H2SO4, was correlated with the configurationally
known (R)-(+)-4,4,4-trifluoro-3-aminobutanoic acid 5,2a in order to assign absolute configurations to the
β-aminoacids 3.
The ring-opening products indicate that reactions proceed with high regio- and stereoselectivity:
nucleophilic attack occurs at the C-2 ring-carbon atom affording only one regioisomer, a β-aminoacid,
in a single diastereoisomeric form. Analytical and spectroscopic data of compounds 3a–h are in close
agreement with the structures. The results are summarised in Table 1.
By treating racemic 2a with dry HCl in ethyl ether at room temperature for 2 h (entry 1), only one
1
product, identified by H NMR spectroscopy as ethyl 3-benzylamino-2-chloro-4,4,4-trifluorobutanoate
3a, was obtained as its hydrochloride, which, after treatment with 1 M NaOH, afforded the pure α-
chloro-β-trifluoromethyl-β-alanine 3a in 94% overall yield.
The same C-2 nucleophilic attack at 2a was observed by reaction with MgBr2 in an anhydrous THF
solution of H2SO4 (entry 2). After 10 min at −10°C, the reaction mixture yielded ethyl 3-benzylamino-
2-bromo-4,4,4-trifluorobutanoate 3b as a single stereoisomer (99%). Interestingly, when the reaction
mixture was allowed to warm up or to react longer (entry 3), 3b was obtained as a mixture of syn/anti
stereoisomers in a variable ratio, indicative of an easy epimerisation under these reaction conditions.
Hydrogenation of 3b, with Pd–C (10%) in ethyl acetate and acetic acid, afforded ethyl 3-benzylamino-
4,4,4-trifluorobutanoate 3c in 67% yield.
Trifluoroacetolysis of 2a at 80°C for 2 h (entry 4) produced the regioisomer ethyl 3-benzylamino-2-
1
hydroxy-4,4,4-trifluorobutanoate 3d in 87% yield and in a single stereoisomeric form, identified by H
NMR spectroscopy as the trifluoroacetate salt. From the salt, 3d was recovered in 96% yield by treatment
with 1 M NaOH. Hydrogenation of 3d, with Pd–C (10%) in ethanol and acetic acid, afforded ethyl 3-
amino-2-hydroxy-4,4,4-trifluorobutanoate 3e in 83% yield.
By analogy, trifluoroacetolysis of (+)-2a (ee 83%) yielded (+)-3d which, upon debenzylation, afforded
ethyl (+)-3-trifluoromethylisoserinate 3e (ee 83%) in 73% overall yield. The corresponding levorotatory

2364
P. Davoli et al. / Tetrahedron: Asymmetry 10 (1999) 2361–2371
Table 1
α-Functionalised β-aminoacids from nucleophilic ring-opening of aziridine 2a,c,d
enantiomer 3g as its methyl ester (ee >98%) was obtained in 75% overall yield from (−)-2c (ee >98%)
following the same procedure (entry 5).
Aziridine 2d, by treatment with trifluoroacetic acid at 70°C for 4 h (entry 6), yielded the regioisomer
ethyl 3-trifluoroacetamino-2-hydroxy-4,4,4-trifluorobutanoate 3h in 91% yield, as a single diastereo-
isomer as indicated by 1H NMR spectroscopy. The isolated product 3h suggests the formation of an α-
trifluoroacetoxy intermediate followed by an intramolecular trifluoroacetyl migration from the oxygen to
the nitrogen as already observed for other N-unsubstituted aziridines.4b
Since aziridine nucleophilic ring-opening reactions are reported to take place generally via SN2
displacement,4b we were able to infer the anti relative configuration for derivatives 3a,b,d–h. This
assignment was unequivocally confirmed through their transformation into the β-lactam derivatives 4
(Scheme 2).
Scheme 2.
2.3. β-Lactam synthesis
A well-known procedure, via Grignard-mediated intramolecular cyclisation,8b,11 was followed for
the synthesis of trans-β-lactams 4a,b from β-aminoacids 3a,e. For derivative 3e in particular, the
necessary protection of the hydroxy group was carried out, before cyclisation, by treatment with t-
butyldimethylsilylchloride (TBDMSCl) in CH2Cl2 and in the presence of 4-N,N-dimethylaminopyridine
(DMAP).

P. Davoli et al. / Tetrahedron: Asymmetry 10 (1999) 2361–2371
2365
In the presence of methyl magnesium iodide at −12°C, cyclisation of 3a occurred quickly: after 5 min,
4a was recovered in 96% yield. By treatment of protected 3e with methyl magnesium iodide at −12°C
and then at room temperature for 12 h, 4b was obtained in 68% chemical yield.
1
The structures of β-lactams 4a and 4b were determined by H NMR and MS spectroscopies: the
relative trans configuration was assigned on the basis of the JH3–H4 coupling constant values (J=1.8
Hz).7 trans Stereochemistry of the β-lactams confirms unambiguously the anti relative configurations of
β-aminoacids 3 and underlines the stereoselectivity of the ring-opening reactions of trans-N-benzyl-3-
trifluoromethyl-2-ethoxycarbonylaziridine 2a. The regiospecific C-2 attack of nucleophiles at 2a might
be attributed to the strong electron-withdrawing effect of the trifluoromethyl group as well as to the
electrostatic repulsion between the trifluoromethyl group and nucleophiles, which prevent C-3 attack.12
2.4. Chemical correlation
The absolute configurations of optically active anti-α-functionalised-β-aminoacids 3, as well as of
aziridine (+)-2a, were assigned by chemical correlation of (+)-3b with the configurationally known2a
(R)-(+)-4,4,4-trifluoro-3-aminobutanoic acid 5 (Scheme 3).
Scheme 3.
Following the procedure described above for racemic 3b, nucleophilic ring-opening of (+)-2a (ee
83%) with MgBr2 afforded (+)-3b in a single anti stereoisomeric form. Catalytic hydrogenation of (+)-
3b, until reductive debromination (20 min) and N-debenzylation (16 h) took place, yielded ethyl 4,4,4-
trifluoro-3-aminobutanoate, which was hydrolysed (6N HCl, 100°C, 4 h) to obtain (+)-4,4,4-trifluoro-3-
aminobutanoic acid 5.
The absolute configuration R of (+)-5 is known from the literature:2a since the chemical transforma-
tions reported in Scheme 3 do not involve the C-3 stereocentre of (+)-2a and (+)-3b, we must deduce
for this stereocentre the same configuration as (+)-5, i.e. configuration 3R for (+)-2a and 3S for (+)-3b.
Owing to the trans relative stereochemistry of aziridine (+)-2a and the anti relative stereochemistry of
(+)-3b, we are able to infer the 2R,3R-configuration for (+)-2a and the 2S,3S-configuration for (+)-3b.
Therefore, anti-isoserinates (+)-3d and (+)-3e, obtained from (2R,3R)-(+)-2a, must have 2S,3R absolute
configurations.
3. Conclusion
trans-N-Benzyl-3-trifluoromethyl-2-ethoxycarbonylaziridine 2a, easily obtainable in high chemical
yield from the commercial trans ethyl γ,γ,γ-trifluorocrotonate, can be resolved by CAL-catalysed
enzymatic ester-function hydrolysis in highly optically active form. This compound proved to be a
versatile intermediate for the regio- and stereoselective synthesis of fluorinated anti-α-functionalised-
β-aminoacids, such as trifluoromethylisoserinates, trifluoro-β-alanine, and for the synthesis of trans-
trifluoromethyl-β-lactams. Starting from optically active aziridines 2, enantiomerically pure isoserinates
can be obtained in high overall chemical yield. The present synthetic method thus provides a useful entry
into the stereoselective preparation of optically active fluorinated β-aminoacids and β-lactams.

2366
P. Davoli et al. / Tetrahedron: Asymmetry 10 (1999) 2361–2371
4. Experimental
1H NMR spectra were recorded on a Bruker AMX 400-WB or DPX-200 spectrometer. Chemical shifts
are reported in δ values from TMS as internal standard (s, singlet; d, doublet; m, multiplet; q, quartet;
t, triplet; br, broad signal). Coupling constants (J) are given in hertz. Optical rotations were measured at
20°C on a Perkin–Elmer 241 polarimeter. GLC analyses were performed on a Hewlett–Packard 5890 A
gas chromatograph on a DB-1 column (30×0.53 mm I.D. and 5 µm film phase) from J&W Scientific,
with helium as carrier gas. The enantiomeric excesses (ees) were evaluated on a chiral B-DEX 120
column (30×0.25 mm I.D. and 0.25 µm film phase) from Supelchem. Mass spectra were determined on
a Finnigan Mat SSQA mass spectrometer (EI, 70 eV). Elemental analyses were performed with a Carlo
Erba elemental analyser. Chromatographic purification of the compounds was performed on silica gel (φ
0.05–0.20 mm). Ethyl trans-4,4,4-trifluoro-2-butenoate and Candida antarctica lipase were purchased
from Aldrich.
4.1. Ethyl 2,3-dibromo-4,4,4-trifluorobutanoate 1
To a stirred solution of ethyl trans-4,4,4-trifluoro-2-butenoate (5.0 g, 29.7 mmol) in carbon tetrachlo-
ride (90 mL), bromine (1.7 mL, 33.1 mmol) was slowly added at room temperature and the solution was
heated at gentle reflux for 5 h. Thereafter, the solvent was removed in vacuo and the oily residue (9.0 g,
1
92% yield) proved to be a mixture of syn/anti isomers which was used without further purification. H
NMR (CDCl3): major isomer (91%): 1.37 (3H, t, J=7.1), 4.35 (2H, q, J=7.1), 4.55 (1H, d, J=10.6),
4.72 (1H, dq, J=10.6, 6.3); minor isomer (9%): 1.36 (3H, t, J=7.1), 4.34 (2H, q, J=7.1), 4.74 (1H,
d, J=6.3), 4.88 (1H, quintet, J=6.3). Both isomers showed the following mass fragmentation: MS,
m/z: 331–329–327 [(M+1)+], 330–328–326 (M+), 302–300–298, 285–283–281, 257–255–253, 176–174,
157–155, 123, 110, 108, 95, 69 (100).
4.2. (ꢀ)-trans-1-Benzyl-3-trifluoromethyl-2-ethoxycarbonylaziridine 2a
Ethyl 2,3-dibromo-4,4,4-trifluorobutanoate 1 (8.96 g, 27.3 mmol) in absolute ethanol (25 mL) was
slowly added to a cooled solution (−5°C) of benzylamine (10.5 mL, 96.1 mmol) in the same solvent
(100 mL) with vigorous stirring over a period of 20 min. The cooling bath was then removed and the
mixture allowed to react for 18 h. The solvent was removed under reduced pressure and diethyl ether
(180 mL) was added to the residue; the precipitate (benzylammonium hydrobromide) was filtered off
and the solution was washed with aqueous HCl (3%, 150 mL), with water (80 mL) and dried (MgSO4).
After filtration the solvent was removed under reduced pressure and the pale yellow oily residue was
1
distilled (76–78°C/0.4 mmHg) to afford aziridine 2a (6.70 g, 90% yield) as a colourless oil. H NMR
(CDCl3): 1.18 (3H, t, J=7.1), 2.93 (1H, dq, J=2.3, 5.0), 2.98 (1H, d, J=2.3), 3.92 (1H, d, J=13.6), 4.07
(1H, d, J=13.6), 4.14 (2H, q, J=7.1), 7.20–7.39 (m, 5H, Ph); MS, m/z: 273 [M+], 272, 244, 204, 200,
180, 158, 141, 130, 105, 104, 91 (100), 77, 65.
4.3. Enzymatic resolution of (ꢀ)-2a
Racemic 2a (500 mg, 1.83 mmol) was added to 0.1 mol dm−3 potassium phosphate buffer [40 mL
containing NaCl (0.1 mol dm−3), pH 7.5] at 37°C and treated with Candida antarctica lipase (10 mg)
with vigorous mechanical stirring. After 30 min, the reaction mixture was extracted with diethyl ether
(3×30 mL); the combined organic layers dried over magnesium sulphate and concentrated under reduced

P. Davoli et al. / Tetrahedron: Asymmetry 10 (1999) 2361–2371
2367
pressure, yielded a crude residue which was purified by column chromatography (light petroleum:diethyl
ether, 7:3, as eluent) to afford 272 mg of (2R,3R)-(+)-2a (54% yield), [α]D +69.6 (c 1.7, CHCl3), ee
83%. Spectroscopic data are identical to those reported for the racemic form. The aqueous phase of the
enzymatic resolution was treated with HCl 10% until pH 1, extracted with ethyl acetate (4×30 mL) and
dried (Na2SO4). After filtration, the solvent was removed under reduced pressure to afford (2S,3S)-(−)-2b
as a fine powder (154 mg, 35%), [α]D −55.3 (c 0.5, CHCl3), ee >98%, mp 133–135°C (from methanol).
1H NMR (DMSO-d6): 2.95 (2H, dq, J=2.6, 0.3), 3.32 (1H, dq, J=2.6, 5.4), 3.99 (2H, s), 7.2–7.4 (5H, m).
The acid (2S,3S)-(−)-2b (154 mg, 0.60 mmol) was dissolved in ethyl acetate and treated with
diazomethane in ether and concentrated under reduced pressure to afford the aziridine (2S,3S)-(−)-2c
(163 mg, 100%) as a colourless oil, [α]D −101.4 (c 1.5, CHCl3), ee >98%. 1H NMR (CDCl3): 3.00 (1H,
dq, J=2.4, 5.0), 3.04 (1H, d, J=2.4), 3.76 (3H, s), 3.97 (1H, d, J=13.6), 4.13 (1H, d, J=13.6), 7.33–7.39
(5H, m); MS, m/z: 259 [M+], 258, 244, 228, 200, 190, 180, 158, 130, 123, 105, 104, 91 (100), 77, 69, 65.
4.4. trans-3-Trifluoromethyl-2-ethoxycarbonylaziridine 2d
A solution of 2a (1.00 g, 3.66 mmol) in ethanol (7 mL) and acetic acid (2 mL) was stirred at
room temperature with Pd 10% on carbon (50 mg) under 1 atm of hydrogen until absorption of
the required volume (90 mL within 1 h). The suspension was treated with aqueous NaHCO3 until
gas evolution ceased, and was then filtered and extracted with diethyl ether. The collected organic
phases were dried over Na2SO4 and concentrated. The residue was purified by column chromatography
(light petroleum:diethyl ether, 9:1, as eluent). The fractions containing aziridine were collected and
concentrated at room temperature affording pure 2d (583 mg, 87%) as a slightly volatile colourless oil.
1H NMR (CDCl3): 1.37 (3H, t, J=7.2), 1.73 (1H, br), 2.84 (1H, dd, J=2.2, 7.9), 2.91 (1H, ddq, J=7.2,
2.2, 5.0), 4.31 (2H, dq, J=1.6, 7.2); MS, m/z: 184 [M+1]+, 183, 155, 138, 137, 118, 110, 109 (100), 90,
86, 82, 70.
4.5. Ethyl 3-benzylamino-2-chloro-4,4,4-trifluorobutanoate 3a
Anhydrous HCl was gently bubbled for 10 min into a cooled (−5°C) solution of the aziridine 2a (1.7
g, 6.2 mmol) in anhydrous diethyl ether (80 mL). After a few minutes a precipitate appeared in the
form of white crystals, and the reaction mixture was vigorously stirred until a TLC analysis showed that
the aziridine had disappeared (2 h). The solvent was removed in vacuo and the crystalline residue was
washed with diethyl ether, to afford compound 3a as the hydrochloride (2.08 g, 96%). Mp 119–121°C.
Anal. calcd for C13H16Cl2F3NO2: C, 45.06; H, 4.62; N, 4.04%; found: C, 45.21; H, 4.71; N, 4.11.
The hydrochloride (1 g, 2.90 mmol) was treated with 1 M NaOH (5 mL) and extracted with diethyl
ether (3×10 mL); the collected organic phases were dried over MgSO4, filtered and the solvent removed
to afford the α-chloro-β-amino-ester 3a as a pale-yellow oil (0.88 g, 98%). 1H NMR (CDCl3): 1.33 (3H,
t, J=7.1), 2.08 (1H, b), 3.83 (1H, m), 3.99 (1H, dd, J=6.0, 13.1), 4.06 (1H, dd, J=4.5, 13.1), 4.30 (2H, dq,
J=1.3, 7.1), 4.51 (1H, d, J=6.2), 7.2–7.4 (5H, m); MS, m/z: 312–310 [M+], 310–308, 282–280, 275–273,
242–240, 226, 204, 188 (100), 186, 160–158, 106, 91.
4.6. Ethyl 3-benzylamino-2-bromo-4,4,4-trifluorobutanoate 3b
A solution of H2SO4 in anhydrous THF (5 mL) was slowly dropped into a stirred solution of
magnesium bromide (674 mg, 3.66 mmol) and aziridine 2a (1 g, 3.66 mmol) in anhydrous THF (40
mL), the temperature being kept at below −10°C. After 10 min the reaction mixture was diluted with

2368
P. Davoli et al. / Tetrahedron: Asymmetry 10 (1999) 2361–2371
diethyl ether (200 mL), washed with 5% NaHCO3, with water and dried over MgSO4. The solvent was
removed by distillation in vacuo at room temperature and the colourless oily residue (1.29 g, 99%) proved
to be 3b in the single anti diastereoisomeric form. 1H NMR (CDCl3): 1.30 (3H, t, J=7.1), 2.15 (1H, b),
3.74 (1H, quintet, J=6.9), 3.96 (1H, d, J=12.8), 4.06 (1H, d, J=12.8), 4.26 (2H, dq, J=2.0, 7.1), 4.41 (1H,
d, J=6.6), 7.2–7.4 (5H, m); MS, m/z: 354–356 [(M+1)+], 353–355, 284–286, 274, 204, 186, 181, 158,
106, 91 (100), 69, 65.
Warming up the reaction mixture at room temperature for 1 h before quenching with NaHCO3, the
product 3b was recovered as a mixture of syn/anti stereoisomers, which were separated by careful
chromatography (light petroleum:diethyl ether, 6:4), to afford the previously described anti isomer (57%)
and the syn isomer (37%). syn Isomer, 1H NMR (CDCl3): 1.27 (3H, t, J=7.3), 2.15 (1H, b), 3.85 (1H, dq,
J=4.1, 6.9), 3.93 (1H, d, J=13.2), 4.02 (1H, d, J=13.2), 4.24 (2H, dq, J=2.7, 7.1), 4.66 (1H, d, J=4.1),
7.2–7.4 (5H, m).
4.7. Ethyl (2S,3S)-(+)-3-benzylamino-2-bromo-4,4,4-trifluorobutanoate 3b
The reaction of (+)-2a (500 mg, 1.83 mmol, ee 83%) with magnesium bromide (337 mg, 1.83 mmol),
carried out as described for racemic 2a, yielded (+)-3b (640 mg, 99%), [α]D +12.0 (c 1.3, CHCl3).
4.8. Ethyl 3-benzylamino-4,4,4-trifluorobutanoate 3c
A solution of 3b (425 mg, 1.20 mmol) in ethyl acetate (8 mL) and acetic acid (1 mL) was stirred at room
temperature with Pd 10% on carbon (50 mg) under 1 atm of hydrogen until absorption of the required
volume (20 min; hydrogenation carried out for 16 h showed also N-debenzylation). The suspension
was treated with aqueous NaHCO3 until gas evolution ceased, and was then filtered and extracted with
ethyl acetate. The collected organic phases were dried over Na2SO4 and concentrated in vacuo. The oily
residue was purified by column chromatography (light petroleum:diethyl ether, 9:1, as eluent) to afford
1
the title compound 3c as a colourless oil (220 mg, 67%). H NMR (CDCl3): 1.27 (3H, t, J=7.1), 1.64
(1H, b), 2.51 (1H, dd, J=9.4, 15.5), 2.69 (1H, dd, J=4.2, 15.5), 3.66 (1H, ddq, J=4.2, 9.4, 7.2), 3.88 (1H,
d, J=13.0), 4.03 (1H, d, J=13.0), 4.18 (2H, dq, J=2.2, 7.1), 7.2–7.4 (5H, m); MS, m/z: 276 [(M+1)+],
274, 228, 206, 188, 186, 184, 159, 106 (100), 91, 77, 65.
4.9. Ethyl 3-benzylamino-2-hydroxy-4,4,4-trifluorobutanoate 3d
A solution of the aziridine 2a (2 g, 7.3 mmol) in trifluoroacetic acid (15 mL) was stirred at 80°C
for 2 h. The reaction mixture, concentrated in vacuo, afforded an light-brown oil which, upon treatment
with wet diethyl ether immediately yielded a solid precipitate; this latter was recovered by filtration and
re-crystallised from CH2Cl2, to afford a white crystalline compound (2.48 g, 87%), identified as the
trifluoroacetate salt of the title compound, mp 94–95°C. Anal. calcd for C15H17F6NO5: C, 44.43; H,
4.23; N, 3.45%; found: C, 44.62; H, 4.32; N, 3.46. 1H NMR (acetone-d6): 1.26 (3H, t, J=7.0), 3.74 (1H,
dq, J=4.0, 7.7), 4.11 (2H, s), 4.24 (2H, q, J=7.0), 4.64 (1H, dq, J=4.0, 1.1), 6.55 (3H, b), 7.24–7.50 (5H,
m); MS, m/z: 292 [M+], 291, 290, 218, 189, 188, 106, 91 (100).
The salt (1 g, 2.47 mmol) was treated with 1 M NaOH (5 mL) and the solution extracted with diethyl
ether (3×10 mL); the collected organic phases were dried over MgSO4, filtered and the solvent removed
1
to afford the crystalline amino-ester 3d, mp 96–97°C (0.69 g, 96%). H NMR (CDCl3): 1.32 (3H, t,
J=7.1), 2.18 (1H, b), 3.23 (1H, b), 3.59 (1H, dq, J=3.3, 7.3), 3.98 (1H, d, J=13.3), 4.08 (1H, d, J=13.3),

P. Davoli et al. / Tetrahedron: Asymmetry 10 (1999) 2361–2371
2369
4.30 (2H, dq, J=0.7, 7.1), 4.46 (1H, dq, J=3.3, 1.0), 7.25–7.45 (5H, m); MS, m/z: 292 [M+], 291, 290,
218, 189, 188, 106, 91 (100).
4.10. Ethyl 3-amino-2-hydroxy-4,4,4-trifluorobutanoate 3e
A solution of 3d (2.48 g, 6.12 mmol) in ethanol (10 mL) and acetic acid (5 mL) was stirred at room
temperature with Pd 10% on carbon (125 mg) under 1 atm of hydrogen until absorption of the required
volume (150 mL within 2 h). The catalyst was then removed by filtration, the solution was poured into
aqueous NaHCO3 (60 mL) and solid NaHCO3 was added until gas evolution ceased. The resulting
suspension was extracted with diethyl ether (3×50 mL) and the collected organic phases were dried
(MgSO4). The solvent was removed in vacuo and the residue purified by column chromatography (n-
hexane:diethyl ether, 1:1, as eluent) to yield 3e (1.02 g, 83%) as white crystals, mp 50–51°C. Anal. calcd
1
for C6H10F3NO3: C, 35.81; H, 5.01; N, 6.96%; found: C, 36.02; H, 5.14; N, 6.83. H NMR (CDCl3):
1.36 (3H, t, J=7.2), 2.25 (3H, b), 3.65 (1H, dq, J=3.5, 7.4), 4.32 (2H, dq, J=0.6, 7.2), 4.41 (1H, dq, J=3.5,
1.1); MS, m/z: 202 [(M+1)+], 128, 104 (100), 98, 80, 76, 59, 58.
4.11. Ethyl (2S,3R)-(+)-3-amino-2-hydroxy-4,4,4-trifluorobutanoate 3e
The reaction of (2R,3R)-(+)-2a (135 mg, 0.51 mmol, ee 83%) with trifluoroacetic acid (2 mL), carried
out as described for racemic 2a, yielded (2S,3R)-(+)-3d as a crystalline white solid, [α]D +11.8 (c
1.7, CHCl3). Subsequent debenzylation of (2S,3R)-(+)-3d, following the same procedure described for
racemic 3d, afforded (2S,3R)-(+)-3e (72 mg, 73% overall yield) as a low-melting solid, mp 32–35°C,
[α]D +15.8 (c 1.6, CHCl3), ee 83%.
4.12. Methyl (2R,3S)-(−)-3-benzylamino-2-hydroxy-4,4,4-trifluorobutanoate 3f
Trifluoroacetolysis of (2S,3S)-(−)-2c (130 mg, 0.5 mmol), ee >98%, carried out as described for the
synthesis of 3d, afforded (2R,3S)-(−)-3f (170 mg, 91%) as a crystalline white solid, mp 86–87°C, [α]D
−11.3 (c 0.6, CHCl3), ee >98%. 1H NMR (CDCl3): 2.04 (1H, b), 3.01 (1H, b), 3.73 (1H, dq, J=3.3, 7.3),
4.04 (1H, d, J=13.6), 4.16 (1H, d, J=13.6), 4.53 (1H, dq, J=3.3, 0.8), 7.20–7.45 (5H, m); MS, m/z: 278
[(M+1)+], 218, 216, 208, 188, 106, 91 (100), 65.
4.13. Methyl (2R,3S)-(−)-3-amino-2-hydroxy-4,4,4-trifluorobutanoate 3g
Debenzylation of (2R,3S)-(−)-3f (170 mg, 0.45 mmol, ee >98%) in methanol (0.75 mL) and acetic
acid (0.45 mL) was stirred at room temperature with Pd 10% on C (15 mg) under 1 atm of hydrogen until
absorption of the required volume (4 h). Following the work-up procedure described for the synthesis of
3e, (2R,3S)-(−)-3g was obtained (70 mg, 82%), [α]D −22.4 (c 0.7, CHCl3), ee >98%. 1H NMR (CDCl3):
1.68 (3H, b), 3.65 (1H, dq, J=3.4, 7.4), 3.94 (3H, s), 4.43 (1H, d, J=3.4); MS, m/z: 188 [(M+1)+], 170,
128, 108, 98, 90 (100), 78, 59.
4.14. Ethyl 3-trifluoroacetamino-2-hydroxy-4,4,4-trifluorobutanoate 3h
A solution of the aziridine 2d (100 mg, 0.55 mmol) in trifluoroacetic acid (2 mL) was stirred at 70°C for
4 h; the reaction mixture was concentrated in vacuo and the residue purified by column chromatography
(n-hexane:diethyl ether, 4:6, as eluent) to afford the title compound (147 mg, 91%) as a white solid, mp

2370
P. Davoli et al. / Tetrahedron: Asymmetry 10 (1999) 2361–2371
73–74°C. Anal. calcd for C8H9F6NO4: C, 32.32; H, 3.03; N, 4.71%; found: C, 31.85; H, 3.08; N, 4.41.
1H NMR (CDCl3): 1.39 (3H, t, J=7.2), 3.32 (1H, b), 4.39 (2H, dq, J=0.8, 7.2), 4.43 (1H, dq, J=3.2, 1.5),
5.11 (1H, ddq, J=10.2, 3.2, 6.7), 7.13 (1H, b); MS, m/z: 298 [(M+1)+], 280, 241, 224, 204, 186, 175, 158,
114, 103 (100), 75, 68.
4.15. trans-1-Benzyl-3-chloro-4-trifluoromethyl-2-azetidinone 4a
A freshly prepared solution of methyl magnesium iodide (4.29 mmol) in anhydrous diethyl ether (10
mL), was slowly added to a stirred solution of 3a (884 mg, 2.86 mmol) in anhydrous diethyl ether
(10 mL) under a stream of nitrogen, at a carefully controlled temperature of −12°C. The mixture was
stirred for a further 5 min, thereafter the slurry was quenched with satd NH4Cl, and extracted with
diethyl ether; the collected organic phases were washed with aqueous NaHCO3, with water and dried
over Na2SO4. The filtered solution was concentrated under reduced pressure and the residue purified by
column chromatography (light petroleum:diethyl ether, 8:2, as eluent) to yield 4a as a colourless oil (723
mg, 96%). 1H NMR (CDCl3): 3.86 (1H, dq, J=1.8, 5.7), 4.07 (1H, d, J=15.1), 4.86 (1H, d, J=1.8), 4.95
(1H, d, J=15.1), 7.2–7.5 (5H, m); MS, m/z: 265–263 [M+], 245–243, 227, 133, 132, 123, 105, 104, 92,
91 (100), 77, 65.
4.16. trans-3-(t-Butyldimethylsilyloxy)-4-trifluoromethyl-2-azetidinone 4b
Before cyclisation, 3e was protected as TBDMS-ether as follows: t-butyldimethylsilylchloride (280
mg, 1.85 mmol) in CH2Cl2 (1 mL) was added to a solution of 3e (107 mg, 0.53 mmol) and 4-N,N-
dimethylaminopyridine (273 mg, 2.23 mmol) in anhydrous CH2Cl2 (2 mL) at −5°C, and the solution
was stirred for 15 min. Thereafter the solution was diluted with CH2Cl2 (5 mL), washed with water and
dried (MgSO4). The solvent was removed in vacuo and the residue purified by column chromatography
(light petroleum:diethyl ether, 8:2, as eluent), to afford ethyl 3-amino-2-(t-butyldimethylsilyloxy)-4,4,4-
trifluorobutanoate (117 mg, 70%) as a colourless oil.
A freshly prepared solution of methyl magnesium iodide (0.76 mmol) in anhydrous diethyl ether (5
mL) was slowly added to a stirred solution of the TBDMS-ether (117 mg, 0.37 mmol) in anhydrous
diethyl ether (5 mL) at −12°C under a stream of nitrogen. The mixture was warmed at room temperature
and stirred overnight; thereafter, the slurry was quenched with satd NH4Cl, and extracted with diethyl
ether; the collected organic phases were washed with aqueous NaHCO3, then with water and dried
over Na2SO4. The filtered solution was concentrated under reduced pressure and the residue purified
by column chromatography (light petroleum:diethyl ether, 6:4, as eluent) to yield 4b as a colourless oil
(68 mg, 68%).
1
Ethyl 3-amino-2-(t-butyldimethylsilyloxy)-4,4,4-trifluorobutanoate: H NMR (CDCl3): 0.12 (3H, s),
0.13 (3H, s), 0.95 (9H, s), 1.33 (3H, t, J=7.1), 1.61 (2H, b), 3.65 (1H, m), 4.26 (2H, dq, J=0.7, 7.1), 4.36
(1H, dq, J=4.3, 0.6); MS, m/z: 316 [(M+1)+], 300, 259, 258, 242, 230, 218, 212, 184 (100), 133, 103, 75,
73.
1
trans 3-(t-Butyldimethylsilyloxy)-4-trifluoromethyl-2-azetidinone 4b: H NMR (CDCl3): 0.20 (3H,
s), 0.21 (3H, s), 0.96 (9H, s), 3.94 (1H, dq, 1.8, 6.2), 4.98 (1H, t, 1.8), 5.98 (1H, b); MS, m/z: 270
[(M+1)+], 254, 241, 226, 212 (100), 184, 169, 157, 90, 88, 77, 73.

P. Davoli et al. / Tetrahedron: Asymmetry 10 (1999) 2361–2371
2371
4.17. Chemical correlation
A solution of (+)-3b (500 mg, 1.41 mmol), [α]D +12.0, ee 83%, in ethyl acetate (8 mL) and acetic
acid (1 mL) was stirred at room temperature with Pd 10% on carbon (55 mg) under 1 atm of hydrogen
until absorption of the required volume (70 ml within 16 h). The catalyst was removed by filtration
and the solution washed with aqueous NaHCO3, dried (MgSO4) and filtered; the complete reductive
debromination and debenzylation to ethyl 3-amino-4,4,4-trifluorobutanoate was confirmed by GC/MS
analysis. Ms, m/z: 186 [(M+1)+], 165, 140, 116, 98, 93, 78, 74, 69.
Owing to the high volatility of the aminoester, the organic solution was extracted with 6N HCl (4
mL), and the aqueous phase heated at reflux for 4 h. Thereafter, the solvent was removed under reduced
pressure to afford 4,4,4-trifluoro-3-aminobutanoic acid 5 as a crystalline solid (43% yield), showing [α]D
+21.4 (c 1.6, 6N HCl) (lit:2a (R)-(+)-5 [α]D +27.6, ee >95%).
Acknowledgements
The authors thank the Ministero della Ricerca Scientifica e Tecnologica, Rome, for financial support
and the Centro Interdipartimentale Grandi Strumenti, Università di Modena e Reggio Emilia, for
instrumental measurements.
References
1. (a) Cardillo, G.; Tomasini, C. Chem. Soc. Rev. 1996, 25, 117, and references cited therein. (b) Ojima, I.; Slater, J. C.
Chirality 1997, 9, 487. (c) Ojima, I.; Delaloge, F. Chem. Soc. Rev. 1997, 26, 377.
2. (a) Soloshonok, V. A.; Kirilenko, A. G.; Fokina, N. A.; Shishkina, I. P.; Galushko, S. V.; Kukhar, V. P.; Svedas, V. K.;
Koslova, E. V. Tetrahedron: Asymmetry 1994, 5, 1119. (b) Abouabdellah, A.; Bégué, J. P.; Bonnet-Delpon, D.; Nga, T. T.
T. J. Org. Chem. 1997, 62, 8826. (c) Cole, D. C. Tetrahedron 1994, 50, 9517.
3. Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599.
4. (a) Righi, G.; D’Achille, R.; Bonini, C. Tetrahedron Lett. 1996, 37, 6893, and references cited therein. (b) Antolini, L.;
Bucciarelli, M.; Caselli, E.; Davoli, P.; Forni, A.; Moretti, I.; Prati, F.; Torre, G. J. Org. Chem. 1997, 62, 8784, and
references cited therein.
5. Davies, F. A.; Reddy, G. V.; Liang, C. H. Tetrahedron Lett. 1997, 38, 5139.
6. Bunnage, M. E.; Burke, A. J.; Davies, S. G.; Goodwin, C. J. Tetrahedron: Asymmetry 1994, 5, 203.
7. Fujisawa, T.; Hayakawa, R.; Shimizu, M. Tetrahedron Lett. 1992, 33, 7903.
8. (a) Guanti, G.; Banfi, L.; Narisano, E. Synthesis 1985, 609. (b) Bevilacqua, P. F.; Keith, D. D.; Roberts, J. L. J. Org. Chem.
1984, 49, 1430.
9. Prati, F.; Moretti, I.; Forni, A.; Torre, G.; Rozhkov, V. V.; Makarov, K. N.; Chervin, I. I.; Kostyanovsky, R. G. J. Fluorine
Chem. 1998, 89, 177.
10. Sih, C. J.; Wu, S. H. Topics in Stereochemistry; Eliel, E. L.; Wilen, S. H., Eds.; Wiley: Chichester, 1989; Vol. 19, p. 63.
11. Backes, J. Houben-Weyl Methoden der Organischen Chemie, Klamann, D., Ed.; Georg Thieme Verlag: Stuttgart, Vol. E
16b, 1991; p. 31.
12. (a) Katagiri, T.; Ihara, H.; Takahashi, M.; Kashino, S.; Furuhashi, K.; Uneyama, K. Tetrahedron: Asymmetry 1997, 8, 2933,
and references cited therein. (b) Kukhar, V. P.; Soloshonok, V. A. In Fluorine-Containing Amino Acids; Wiley: Chichester,
1995.