Novel strategy for the synthesis of fluorinated β-amino acid derivatives from Δ2-oxazolines

Article abstract of DOI:10.1016/S0040-4020(01)00539-7

Racemic and chiral non-racemic β-fluoroalkyl-β-amino acid derivatives have been prepared in two steps starting from 2-alkyl-Δ²-oxazolines and fluorinated imidoyl chlorides. Subsequent chemoselective reduction of the C-masked β-enamino acid derivatives initially formed provided the target β-amino acids. The process takes place with total chemoselectivity, high yields and satisfactory diastereoselectivity.

Full text of DOI:10.1016/S0040-4020(01)00539-7

TETRAHEDRON
Pergamon
Tetrahedron 57 >2001) 6475±6486
Novel strategy for the synthesis of ¯uorinated b-amino acid
derivatives from D2-oxazolines
p
Santos Fustero, Esther Salavert, Belen Pina, Carmen Ramõrez de Arellano and Amparo Asensio
²
Â
Â
   Â
Departamento de Quõmica Organica, Facultad de Farmacia, Avda. Vicente Andres Estelles s/n, Universidad de Valencia, 46100 Burjassot,
Valencia, Spain
Received 19 January 2001; revised 23 February 2001; accepted 2 April 2001
AbstractÐRacemic and chiral non-racemic b-¯uoroalkyl-b-amino acid derivatives have been prepared in two steps starting from 2-alkyl-
D2-oxazolines and ¯uorinated imidoyl chlorides. Subsequent chemoselective reduction of the C-masked b-enamino acid derivatives initially
formed provided the target b-amino acids. The process takes place with total chemoselectivity, high yields and satisfactory diastereoselec-
tivity. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
which derives from an awareness of their unique biomedical
properties.6 For this reason, the development of new prac-
tical synthetic methods for the preparation of ¯uorinated
chiral synthons and the upgrade of the existing ones are
receiving a considerable deal of attention. In particular,
¯uorinated amino acids and amino alcohols not only exhibit
a variety of biological properties, but also are useful and
versatile synthetic intermediates in organic synthesis.7,8
1,3-Difunctionalised compounds are of considerable import-
ance, both as synthetic intermediates and as potential thera-
peutic agents. Among all of them, the b-amino acid unit has
been recognised as one of the most attractive, as a conse-
quence that it can be transformed to yield a broad spectrum
of functionalities, as well as for their increased use as valu-
able intermediates in the design and construction of novel
biologically and medicinally important molecules.1 In this
sense, b-amino acids have shown unique pharmacological
properties both as component of natural occurring
compounds and in free form.2 The former is exempli®ed
by the well-known antitumor agent Taxolw, which contains
an a-hydroxy b-amino acid side chain.3 The latter can be
exempli®ed by the antifungal cis-pentacine, isolated from
bacteria Streptomices setonii.4 b-Amino acids can also form
b-peptides, a new class of promising compounds that are
able to mimic natural a-peptides showing stronger stability
against enzymatic hydrolysis.5
Despite the above-mentioned general biomedicinal bene®ts
of hydrogen replacement by ¯uorine, not much is known
about the chemistry and biological activity of ¯uorine
containing b-amino acids, very likely due to the lack of
methods for their preparation. In fact, there are a limited
number of versatile synthetic routes covering the synthesis
of ¯uorinated b-amino acids mostly as racemates.
In general, two main strategies have been used for the
synthesis of these derivatives, namely, direct ¯uorination
and the building block approach. One example in the former
area was found in 1994 when Davis described the prepara-
tion of a-¯uoro analogs of the C-13 side chain of taxolw.
They were synthesised with poor stereocontrol either by
asymmetric electrophilic ¯uorination of non-¯uorinated a-
amino esters or, alternatively, by Mannich-type reaction of
a-¯uoro-enolates with chiral sul®nimines.9
Because of their importance considerable research efforts
have been devoted in the last two decades, particularly, in
the preparation of enantiopure b-amino acids by using
different synthetic strategies, such as the chiral pool
approach, enzymatic resolutions, diastereoselective reactions
with chiral auxiliaries, and catalytic asymmetric synthesis.1
Regarding the building block approach, several recent
strategies have been developed for the preparation of b-
¯uoroalkyl-b-amino acids. They include the following
Another area of expansion in recent years has to do with
recognition of the utility of ¯uorine-containing molecules,
Â
Â
reports: >i) Begue prepared racemic and chiral non-racemic
syn->3-¯uoroalkyl)isoserinates in good yield but poor
diastereoselectivity from >¯uoroalkyl)imines via ketene±
imine [212] cycloaddition.10 >ii) Uneyama developed a
different protocol for synthesising racemic anti->3-¯uoro-
alkyl)isoserinates, involving the diastereoselective reduction
Keywords: amino acids and derivatives; ¯uorine and compounds; oxazo-
lines; imidoyl halides.
p
Corresponding author. Tel.: 134-96-3864279; fax: 134-96-3864939;
e-mail: santos.fustero@uv.es
Corresponding author regarding X-ray diffraction studies.
²
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020>01)00539-7

6476
S. Fustero et al. / Tetrahedron 57 ,2001) 6475±6486
Scheme 1.
of a-hydroxy-b-imino esters, obtained via intramolecular
rearrangement of imino ethers.11 >iii) Previously, Kitazume
had described in 1993 the ®rst synthesis of racemic b-
>di¯uoromethyl)-b-amino acid derivatives from di¯uoro-
acetaldimine and enol silyl ethers.12 >iv) Another important
route to b-amino acids consists of the asymmetric Michael
addition of ammonia or amines to a,b-unsaturated esters.
However, only a limited number of a- and b->tri¯uoro-
methyl)-b-alanines have been obtained using this strategy.13
In this context, Zanda et al. have applied very recently this
methodology to the synthesis, both in solution and solid-
phase, of novel enantiomerically pure, partially-modi®ed
retro and retro-inverso C[NHCH>CF3)]-peptides.14 >v)
Soloshonok developed a conceptually different method-
ology for the synthesis of non-racemic b-¯uoroalkyl-b-
amino acids.15 The procedure is based on the stereoselective
biomimetic transamination of b-¯uoroalkyl-b-keto esters
and it implies a base-catalysed [1,3]-proton shift reaction
followed by hydrolysis and biocatalytic resolution by peni-
cillin acylase. Alternative procedures using chiral bases15c
and chiral amines15d have been also reported.
As a part of our program to study the synthesis and reac-
tivity of ¯uorinated and non-¯uorinated 1,3-difunctionalised
derivatives,18 we have undertaken the development of new
and more effective strategies for the preparation of enantio-
pure ¯uorinated b-amino acid derivatives. Our synthetic
efforts have focused on the carboxylic acid moiety as
the site for introducing functionalities that both block this
reactive position and can simultaneously act as a chiral
auxiliary. Heterocyclic systems such as D2-oxazolines,
which have often shown their utility in asymmetric synthe-
sis, ful®l both these requirements.19
Our group has previously reported a simple entry to racemic
non-¯uorinated b-amino acids starting from 2-alkyl-D2-
oxazolines.20 The process, however, appears to be restricted
to aromatic systems and in the case of chiral non-racemic
derivatives, we observed, in general, poor stereocontrol. Our
present goal is to generalise the process to other systems, in
particular, to ¯uorine derivatives. We thus now present an
ef®cient two-step method for the preparation of enantiopure
¯uorinated b-amino acid derivatives by reduction of
masked b-enamino acids 4, which have been derived from
2-alkyl-D2-oxazolines 1 and imidoyl halides 2.
Finally, an attractive approach to enantiopure b-amino acids
involves the chemo- and stereoselective reduction of chiral
non-racemic enamines. However, although enamines are
well-known intermediates in synthetic organic chemistry,
to the best of our knowledge, no examples have been
described regarding the preparation of enantiopure ¯uori-
2. Results and discussion
Our strategy is based on the reaction of a-metalated 2-alkyl-
D2-oxazolines with acylimidoyl species to furnish initially
masked b-enamino acid derivatives 3. Thus, the treatment
of 2-methyl >or 2-ethyl)-D2-oxazolines 1 >1.0 equiv.) with
2.0 equiv. of lithium diisopropylamide >LDA) followed by
¯uorinated imidoyl chlorides 221 >1.1 equiv.) led cleanly to
the corresponding C-oxazoline protected b-enamino acids
3, in overall yield of 69±92%. In general, compounds 3
were isolated as a mixture of imino±enamino tautomers22
>Scheme 1). Table 1 summarises the obtained results.
³
nated b-amino acids by using this strategy. In fact, only
three examples related to their synthesis in racemic form
have appeared in the literature. In 1995, Shen reported the
®rst two examples of racemic b-¯uoroalkyl-b-amino acids
obtained by catalytic hydrogenation with Pd/C of N-benzyl
b-enamino esters.16 Another method for the preparation
of these derivatives is the aforementioned reduction of a-
hydroxy-b-imino esters.11 In this context, we devised very
recently an ef®cient two-step approach for the diastereo-
selective synthesis of racemic syn-a-methyl-b-¯uoroalkyl-
b-amino esters. The reaction is highly diastereoselective
and the approach is based on the chemical reduction of b-
¯uoroalkyl-b-enamino esters, previously obtained from
imidoyl halides and ester enolates.17
In a second step, compounds 3 were reduced to the corre-
sponding protected ¯uorinated b-amino acid derivatives 4.
The study carried out included, ®rst the search of convenient
reducing conditions to produce a chemo- and diastereo-
selective process and second the effect of the chiral
auxiliaries >oxazoline protecting-group and nitrogen sub-
stituent) in the diastereoselectivity of the reaction. In one
hand, the choice of the reducing agent was crucial because
³
Although conceptually, the biomimetic transamination is considered to be
a reducing agent-free reductive amination, we have not included it in this
section.

S. Fustero et al. / Tetrahedron 57 ,2001) 6475±6486
6477
Table 1. Fluorinated C-oxazoline protected b-enamino acids 3 obtained from 2-alkyl-2-oxazolines 1 and imidoyl chlorides 2
Entry
1
2
3
Yield >%)a
Imino:enamino ratiob
RF
R1
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1b
1b
1c
1d
1d
1e
1f
CF3
CF2Cl
CF3
CF2Cl
CF3
CF2CF3
CF2CF3
CF3
CF2Cl
CF3
CF3
p-MeOC6H4
p-MeOC6H4
c-C6H11
3ac
3b
87
66
80
65
80
83
70
72
75
92
82
90
70
60
0:100
0:100
0:100
0:100
0:100
33:66
92:8
0:100
10:90
0:100
25:75
0:100
9:91
3c
3d
>S)-C6H5>Me)CH
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
3ec
3f
3g
>2)-3h
>2)-3i
>1)-3j
>1)-3k
>2)-3l
>2)-3m
>1)-3n
9
10
11
12
13
14
1g
1g
1h
CF3
CF2Cl
CF3
0:100
a
Isolated yield.
b
c
1
Tautomeric ratio estimated by H and/or 19F NMR on the crude reaction mixture.
Lit. Ref. 22a.
our previous results had shown that, with some exception,
only dissolving metals were effective with this class of
derivatives.20 Unfortunately, the use of the system Na/i-
PrOH as reducing agent with compounds 3 afforded a
complex reaction mixture instead of the target b-amino
acids 4. On the other hand, to study the diastereoselectivity
of the process we focused our attention in the effect of the
oxazoline-protecting group as chiral auxiliary; therefore, a
series of 2-alkyl-D2-oxazolines 1d±h >Fig. 1) were chosen.23
conditions provided an almost equimolecular and separable
mixture of racemic syn/anti diastereomers in 60% yield. In
an attempt to improve the diastereoselectivity, we used the
system ZnI2/NaBH4 in CH2Cl2 as solvent >Method B, Table
2), which had been successfully employed in the synthesis
of syn-a-methyl-b-¯uoroalkyl-b-amino esters.17 After 24 h
at room temperature and subsequent work-up, compound 4g
was isolated in good yield. Indeed, the diastereoselectivity
was dramatically increased >de 94%) providing the syn dia-
stereomer as the major product >Scheme 3).
Closely related reductions of ¯uorinated b-enamino esters
had shown that the use of catalytic hydrogenation16 and
borohydride reagents17 were particularly ef®cient. There-
fore, in a ®rst attempt, we tested the catalytic hydrogenation
of achiral derivatives 3 >entries 1±3, 5±7, Table 2). In all
these instances the reactions were performed with palladium
on carbon >5% Pd) using methanol as solvent and at room
temperature for several hours >Method A, Table 2). The
process worked well in most of cases regardless of the
nature of the substituents in 3 and with total chemoselect-
ivity, furnishing compounds 4 in good yields >Scheme 2 and
Table 2).
We next investigated the in¯uence on the diastereoselect-
ivity by employing chiral non-racemic adducts 3, which
locate the chirality either at the nitrogen atom substituent
or at the oxazoline portion.
In the ®rst case, compound 3d [R1ˆ>S)-C6H5>Me)CH, entry
4, Table 1] was chosen as a simple model. The best reduc-
tion conditions found >Method B) were used for this
purpose. Thus, compound 4d >entry 4, Table 2) was
obtained in moderate yield, albeit as a 56:44 non-separable
mixture of diastereomers >Scheme 3).
When two diastereomers were possible as a result of reduc-
tion >R2ˆMe, entry 7, Table 2) the chemoselective hydro-
genation of the enamino moiety using the above-mentioned
This disappointing result turned us to focus on the second
approach. Therefore, a number of chiral non-racemic oxazo-
line derivatives 3h±n >Scheme 2 and Fig. 1) were subjected
Figure 1.

6478
S. Fustero et al. / Tetrahedron 57 ,2001) 6475±6486
Table 2. Fluorinated C-oxazoline protected b-amino acid derivatives 4
Entry
1
RF
CF3
CF2Cl
CF3
CF2Cl
CF3
CF2CF3
CF2CF3
CF3
CF2Cl
CF3
CF3
CF3
CF2Cl
CF3
R1
4
Yield >%)a
Methodb
Diastereomeric ratioc
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1b
1b
1c
1d
1d
1e
1f
p-MeOC6H4
p-MeOC6H4
c-C6H11
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
>72)
>88)90
>85)
60
>86)
>60) 60
>60) 80
>30) 90
70
75
65
A
A,B
A
B
A
A,B
A,B
A,B
B
B
B
±
±
±
>S)-C6H5>Me)CH
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
56:44d
±
±
>45:55) 97:3e
>47:53) 80:20f
78:22f
9
10
11
12
13
14
65:35f
55:45f
1g
1g
1h
>20) 80
90
60
B
B
B
>45:55) 80:20f
70:30f
60:40f
a
Yields of the crude product >not optimised). In parentheses yields corresponding to Method A.
Method A: H2, Pd>C) 5%, MeOH, rt. Method B: ZnI2 >3.0 equiv), NaBH4, CH2Cl2, rt.
Determined from crude mixture >1H- and 19F NMR).
Diastereomeric ratio for adducts bearing the chirality in the nitrogen atom >see, Scheme 3).
Syn/anti diastereomeric ratio for >^)-4g >Method B) >Scheme 3). In parentheses Method A.
4a:4b Diastereomeric ratio.
b
c
d
e
f
Scheme 2.
to reduction conditions Method B. After work-up, good
yields and moderate to good stereocontrol >up to 4:1)
were attained only in the case of oxazolines derived of
>1S,2S)-2-amino-3-methoxy-1-phenyl-1-propanol 1d >entries
8 and 9, Table 2) and >R)-2-amino-3-phenyl-1-propanol 1g
>entries 12 and 13, Table 2). For comparison, catalytic
hydrogenation of compounds >2)-3h and >2)-3l was also
tested; however, this method provided lower yields of
adducts 4h >30%) and 4l >20%). In addition, the
compounds were obtained with no signi®cant asymmetric
Scheme 3.

S. Fustero et al. / Tetrahedron 57 ,2001) 6475±6486
6479
Figure 2. Thermal ellipsoid plot >50% probability level) of 4ma.
induction as an almost equimolecular mixture of a and b
diastereomers.
Surprisingly, when >S)-4-isopropyl-2-methyl-D2-oxazoline
1e, >S)-4-tert-butyl-2-methyl-D2-oxazoline 1f, and >1S,2R)-
1-amino-2-indanol derived 2-methyl-D2-oxazoline 1h
>entries 10, 11 and 14 respectively, Table 2 and Fig. 1)
were used as chiral substrates, poor asymmetric induction
>de 10±30%), lower yields and a non-separable mixture of
4a and 4b diastereomers were observed >Scheme 2 and
Table 2).
Figure 3. In®nite linear chains of 4ma formed through N>2)±H>2)´´´N>1)#
>#: x11, y, z) hydrogen bonds.
C>4)±C>5) bond >Fig. 2), the oxazoline group presents a
gauche and an anti conformation with respect to the p-
methoxy-phenylamino and the CF2Cl groups, respectively.
Isomers 4la, 4lb, 4ha and 4ma >Table 2) were isolated in
the pure form by ¯ash chromatography and puri®ed by
crystallisation from hexane or mixtures of hexane/ethanol
>see, Section 3). Their structures were ascertained by NMR
>1H-, 19F- and 13C) spectroscopy, analyses and/or HRMS.
Ê
The oxazoline ring is planar >mean deviation 0.039 A) and
nearly perpendicular to both p-anisyl and phenyl rings >78.2
and 100.38 dihedral angles, respectively). In the crystal, the
amino group is hydrogen bonded to the oxazoline nitrogen
atom of a different molecule [N>2)±H>2)´´´N>1)# >#: x11, y,
1
For instance, the H NMR spectrum for compound 4la
Ê
Ê
displays characteristic signals at d 2.64 >dd, Jˆ9.6,
14.8 Hz, 1H), 2.83 >dd, Jˆ4.1, 14.8 Hz, 1H) and 4.26 >m,
1H), which correspond to the ABX system of the
CH2CHNH grouping. In the 19F NMR spectrum, the signal
of the CF3 group appear as a doublet at d 276.63 >d,
Jˆ6.4 Hz, 3F). Further analysis of this product by 13C
NMR was in complete agreement with the assigned struc-
ture. The most characteristic feature was a quartet centred at
d 55.5 >q, 2JCFˆ30.9 Hz), which corresponds to the CHNH
carbon atom.
z), N>2)´´´N>1)# 3.187>7) A, H>2)´´´N>1)# 2.33>2) A, N>2)±
H>2)´´´N>1)# 176>5)8]. The N±H´´´N intermolecular hydro-
gen bond forms in®nite linear chains >Fig. 3).
The stereochemical outcome of the reduction of adducts 3
might be rationalised using a cyclic model as indicated in
Fig. 4. It is supposed that ZnI2 coordinates with both nitro-
gen atoms in a six-membered metal chelate, much the way
the related ¯uorinated b-imino esters do.17 The stereodirect-
ing effect of the chiral center at C-4 in the oxazoline ring
plays a signi®cant role in the ®nal stereochemical outcome.
The hydride preferentially attacks the imino group from the
opposite side >Si face for 4ma) of the chiral C-4 substituent.
Thus, complexation of adducts 3 by ZnI2 proved to be useful
in 1,5-asymmetric induction, as shown in Fig. 4 and Table 2.
In order to determine the relative con®guration of the newly
created stereogenic centre at C-2 of the side chain [C>5) in
Fig. 2], we carried out an X-ray diffraction analysis with a
suitable crystal of the major diastereomer of 4m.§ A view of
the solid-state structure for 4ma is depicted in Fig. 2, which
shows that the absolute con®guration of the new stereogenic
centre in 4ma is R, that is, >20R,4R)-4m.
In a last step, enantiopure adducts 4 can be easily trans-
formed into the corresponding N-protected b-amino esters.
Thus, the hydrolysis with HCl 1N and subsequent esterif-
ication of compound >20R,4R)-4l gave N-p-methoxyphenyl
protected methyl and isopropyl b-amino esters >R)-5 with
overall yields of 65 and 60%, respectively >Scheme 4).k
In the crystal the molecule adopts a U shape with both
aromatic rings making a 69.58 dihedral angle. For the
§
Crystallographic data >excluding structure factors) have been deposited
with the Cambridge Crystallographic Data Centre and can be obtained on
request from CCDC, 12 Union Road, Cambridge CB2 1EZ, UK.
k
Further conversion of 5 into N-unprotected b-amino esters could be
carried out by standard procedures. See, for example, Ref. 17.

6480
S. Fustero et al. / Tetrahedron 57 ,2001) 6475±6486
and coupling constants, J, are reported in d ppm and in Hz,
respectively. Carbon multiplicities were established by
DEPT. High-resolution mass spectral data >HRMS), were
obtained at 70 eV by electron impact. Compounds 3a and 3e
have been previously described.22a
Figure 4.
3.2. General procedure for the synthesis of N-substituted
b-enamino-D2-oxazolines 3
In an analogous fashion, acid hydrolysis of >20R,4R)-4l,
followed by reduction using LiAlH4 in THF, at room
temperature provided the ¯uorinated g-amino alcohol
derivative >R)-6, in 70% yield >Scheme 4).
To
a stirred solution of diisopropylamine >2.6 mL,
20 mmol) in THF >15 mL) at 08C was added butyllithium
>2.5 M in hexane, 8.0 mL, 20 mmol). After stirring for
15 min, the solution was cooled to 2788C and 2-alkyl-D2-
oxazoline 1 >10 mmol) in THF >15 mL) was added. The
reaction mixture was stirred for 2 h; then, a solution of the
desired imidoyl chloride 2 >11 mmol) in THF >15 mL) was
slowly added. When TLC analysis showed the disappear-
ance of the starting material, the reaction was quenched by
addition of saturated ammonium chloride solution >30 mL).
The aqueous layer was extracted with methylene chloride
>2£25 mL). The combined organic layers were washed with
brine and dried >Na2SO4). After ®ltration, the solvents were
removed under reduced pressure to furnish the crude
product 3. Puri®cation was carried out as indicated in
each case.
In summary, chiral non-racemic D2-oxazolines have been
used as an effective protecting and chiral auxiliary group
for the chemo and diastereoselective reduction of b-¯uoro-
alkyl-b-enamino acid derivatives. The approach described
herein, which makes use of borohydride reagents, offers a
straightforward synthetic pathway to enantiopure b-¯uoro-
alkyl-b-amino acids in good to excellent yield and
moderate diastereoselectivity. Alternative procedures for
the diastereo- and enantioselective synthesis of these deriva-
tives are in progress and will be reported elsewhere.
3. Experimental
3.1. General
3.2.1. +Z)-1-Chloro+di¯uoro)methyl-2-+4,5-dihydro-1,3-
oxazol-2-yl)-1-ethenyl+4-methoxyphenyl)amine +3b).
White solid, puri®ed by recrystallisation [n-hexane±EtOH
>10:1)]; mp 85±868C; 1H NMR >CDCl3, TMS, 400 MHz) d
10.21 >bs, 1H), 7.15 >d, 2H, Jˆ8.7 Hz), 6.83 >d, 2H,
Jˆ8.7 Hz), 5.29 >s, 1H), 4.25 >t, 2H, Jˆ9.0 Hz), 4.00 >t,
2H, Jˆ9.0 Hz), 3.75 >s, 3H); 19F NMR >CDCl3, 376 MHz)
d 250.92 >s, 2F); 13C NMR >CDCl3, 100 MHz) d 165.5 >s),
THF was distilled under argon from sodium/benzophenone
ketyl as the drying agent. Diisopropylamine, used to gener-
ate LDA, was re¯uxed over KOH, distilled, and stored
Ê
under argon in the presence of 4 A molecular sieves at
48C. Solvents used in extractions, recrystallisations, and
chromatographic columns were distilled prior to use. All
other reagents were commercially available and were used
as received. Compounds were visualised on analytical thin
layer chromatograms >TLC) by UV light >254 nm). Silica
2
158.0 >s), 157.9 >t, JCFˆ25.2 Hz), 131.6 >s), 128.9 >d),
1
122.1 >t, JCFˆ250.8 Hz), 113.6 >d), 83.4 >d), 66.0 >t),
55.3 >q), 54.2 >t); HRMS >EI): Calcd for C13H13F2ClN2O2
302.0633, found 302.0636. Anal. Calcd for
C13H13F2ClN2O2: C, 51.58; H, 4.33; N, 9.25; found C,
51.25; H, 4.44; N, 9.14.
Ê
gel >60 A) for ¯ash chromatography was used for purifying
the products.
All reactions were conducted under dry nitrogen and the
glassware used was oven dried >1208C), evacuated, and
purged with argon. Temperatures are reported as bath
temperatures. Melting points are reported uncorrected and
were measured on a Cambridge Instruments apparatus using
open capillary tubes. Nuclear magnetic resonance spectra
3.2.2. Cyclohexyl[+Z)-2-+4,5-dihydro-1,3-oxazol-2-yl)-1-
tri¯uoromethyl-1-ethenyl]amine +3c). Orange oil, puri®ed
by ¯ash chromatography on deactivated >Et3N 3%) SiO2 [n-
hexane±EtOAc >8:1)]; 1H NMR >CDCl3, TMS, 400 MHz) d
8.61 >d, 1H, Jˆ8.52 Hz), 4.93 >s, 1H), 4.07 >t, 2H,
Jˆ9.1 Hz), 3.86 >t, 2H, Jˆ9.1 Hz), 3.29 >m, 1H), 1.06±
1.84 >m, 10H); 19F NMR >CDCl3, 376 MHz) d 266.46 >s,
3F); 13C NMR >CDCl3, 100 MHz) d 166.1 >s), 153.4 >q,
1
for H-, 13C- and 19F were determined on a Bruker AC-
250, 300 and 400 MHz spectrometer, in CDCl3, using tetra-
methylsilane as an internal standard. Chemical shift values
Scheme 4.

S. Fustero et al. / Tetrahedron 57 ,2001) 6475±6486
6481
2JCFˆ30.5 Hz), 120.9 >q, 1JCFˆ274.4 Hz), 80.7 >d), 65.6 >t),
54.2 >t), 52.9 >d), 34.8 >t), 25.3 >t), 24.6 >t); HRMS >EI):
Calcd for C12H17F3N2O 262.1292, found 262.1298.
oxyphenyl)amine +3h). Yellow oil, puri®ed by ¯ash
chromatography on deactivated >Et3N 3%) SiO2 [n-hex-
ane±EtOAc >3:1)]; a]25 ˆ298.38 >c 0.97, CDCl3); 1H
D
NMR >CDCl3, TMS, 250 MHz) d 10.12 >bs, 1H), 7.21±
7.29 >m, 5H), 7.06 >d, 2H, Jˆ8.9 Hz), 6.75 >d, 2H,
Jˆ8.9 Hz), 5.27 >s, 1H), 5.21 >d, 1H, Jˆ6.7 Hz), 4.16 >m,
1H), 3.70 >s, 3H), 3.56 >dd, 1H, Jˆ9.5, 4.3 Hz), 3.42 >dd,
1H, Jˆ9.6, 6.8 Hz), 3.32 >s, 3H); 19F NMR >CDCl3,
3.2.3. +Z)-[1-+Chloro+di¯uoro)methyl)-2-+4,5-dihydro-1,3-
oxazol-2-yl)-1-ethenyl]-[+1S)-1-phenylethyl]amine +3d).
Pale yellow oil, puri®ed by ¯ash chromatography on deac-
tivated >Et3N 3%) SiO2 [n-hexane±EtOAc >3:1)];
1
a]25 ˆ1342.38 >c 0.92, CDCl3); H NMR >CDCl3, TMS,
235 MHz)
62.8 MHz)
d
263.35 >s, 3F); 13C NMR >CDCl3,
164.9 >s), 158.0 >s), 144.2 >q,
D
400 MHz) d 9.13 >d, 1H, Jˆ9.0 Hz), 7.13±7.26 >m, 5H),
5.02 >s, 1H), 4.83 >m, 1H, Jˆ4.5 Hz), 4.12 >t, 2H,
Jˆ9.0 Hz), 3.94 >t, 2H, Jˆ9.0 Hz), 1.46 >d, 3H,
Jˆ6.5 Hz); 19F NMR >CDCl3, 376 MHz) d 252.59 >d, 1F,
Jˆ169.3 Hz) 255.61 >d, 1H, Jˆ169.3 Hz); 13C NMR
d
2JCFˆ30.5 Hz), 140.7 >s), 131.5 >s), 128.7 >d), 128.5 >d),
1
127.3 >d), 125.6 >d), 122.7 >q, JCFˆ275.0 Hz), 113.8 >d),
2
83.8 >q, JCFˆ5.7 Hz), 82.0 >d), 74.2 >t) 63.3 >d), 59.3 >q),
55.3 >q); HRMS >EI): Calcd for C21H21F3N2O3 406.1504,
found 406.1501. Anal. Calcd for C21H21F3N2O3: C, 62.06;
H, 5.21; N, 6.89; found C, 61.70; H, 5.01; N, 6.58.
2
>CDCl3, 100 MHz) d 166.0 >s), 148.2 >t, JCFˆ26.0 Hz),
1
145.2 >s), 128.9 >d), 128.6 >t, JCFˆ245.2 Hz), 127.2 >d),
3
125.8 >d), 81.7 >t, JCFˆ8.7 Hz), 66.2 >t), 54.8 >t), 54.1
>d), 25.7 >q); HRMS >EI): Calcd for C14H15F2ClN2O
300.0840, found 300.0841.
3.2.7. +Z)-1-Chloro+di¯uoro)methyl-2-[+4S,5S)-methoxy-
methyl-5-phenyl-4,5-dihydro-1,3-oxazol-2-yl-1-ethenyl
+4-methoxyphenyl)amine +3i). Yellow oil, puri®ed by ¯ash
3.2.4. +Z)-2-+4,4-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-1-
+1,1,2,2,2-penta¯uoroethyl)-1-ethenyl+4-methoxyphenyl)
amine +3f). Yellow oil, puri®ed by ¯ash chromatography on
chromatography on deactivated >Et3N 3%) SiO2 [n-hexane±
1
EtOAc >3:1)]; a]25 ˆ270.98 >c 0.78, CDCl3); H NMR
D
>CDCl3, TMS, 400 MHz) d 10.11 >bs, 1H), 7.12±7.30 >m,
5H), 7.10 >d, 2H, Jˆ9.0 Hz), 6.77 >d, 2H, Jˆ9.0 Hz), 5.29
>s, 1H), 5.23 >d, 1H, Jˆ6.5 Hz), 4.16 >m, 1H), 3.73 >s, 3H),
3.57 >dd, 1H, Jˆ9.5, 4.5 Hz), 3.44 >dd, 1H, Jˆ9.8, 7.0 Hz),
3.34 >s, 3H); 19F NMR >CDCl3, 376 MHz) >enamino tauto-
mer): d 250.94 >d, 2F, Jˆ4.5 Hz); >imino tautomer) d
259.50 >d, 2F, Jˆ17.1 Hz); 13C NMR >CDCl3, 100 MHz)
1
deactivated >Et3N 3%) SiO2 [n-hexane±EtOAc >4:1)]; H
NMR >CDCl3, TMS, 250 MHz) >enamino tautomer) d
9.84 >bs, 1H), 7.00 >d, 2H, Jˆ8.6 Hz), 6.73 >d, 2H,
Jˆ8.6 Hz), 5.23 >s, 1H), 3.80 >s, 2H), 3.70 >s, 3H), 1.19
>s, 3H), 1.16 >s, 3H); >imino tautomer) d 6.88 >d, 2H,
Jˆ8.5 Hz), 6.84 >d, 2H, Jˆ8.5 Hz), 3.84 >s, 2H), 3.72 >s,
3H), 3.37 >s, 2H), 1.21 >s, 3H), 1.18 >s, 3H); 19F NMR
>CDCl3, 235 MHz) >enamino tautomer) d 283.37 >s, 3F),
2111.89 >s, 2F); >imino tautomer) d 281.72 >s, 3F),
2116.72 >s, 2F); 13C NMR >CDCl3, 62.8 MHz) >enamino
2
d 165.0 >s), 158.1 >s), 148.5 >t, JCFˆ24.7 Hz), 140.7 >s),
131.4 >s), 129.0 >d), 128.0 >d), 128.4 >d), 125.5 >d), 121.1 >t,
3
1JCFˆ231.0 Hz), 113.7 >d), 82.8 >t, JCFˆ7.7 Hz), 82.1 >d),
74.6 >t) 73.8 >d), 59.3 >q), 55.3 >q); HRMS >EI): Calcd for
C21H21F2ClN2O3 422.1208, found 422.1201.
2
tautomer) d 162.4 >s), 157.7 >s), 141.7 >t, JCFˆ22.3 Hz),
1
132.9 >s), 128.0 >d), 123.0 >qt, JCFˆ278.2 Hz and
1
2JCFˆ32.4 Hz), 114.3 >d), 113.6 >tq, JCFˆ267.2 Hz and
3.2.8. +Z)-2-[+4S)-4-Isopropyl-4,5-dihydro-1,3-oxazol-2-yl]-
1-tri¯uoromethyl-1-ethenyl+4-methoxyphenyl)amine +3j).
Yellow oil, puri®ed by ¯ash chromatography on deactivated
3
2JCFˆ35.4 Hz), 90.4 >t, JCFˆ6.9 Hz), 77.6 >t), 67.2 >s),
55.2 >q), 28.3 >q); >imino tautomer) d 162.4 >s), 157.7 >s),
2
141.7 >t, JCFˆ22.3 Hz), 132.9 >s), 128.0 >d), 123.0 >qt,
>Et3N 3%) SiO2 [n-hexane±EtOAc >4:1)]; a]25 ˆ167.18 >c
D
2
1
1.05, CDCl3); H NMR >CDCl3, TMS, 250 MHz) d 10.31
1JCFˆ278.2 Hz and JCFˆ32.4 Hz), 114.3 >d), 113.6 >tq,
2
3
1JCFˆ267.2 Hz and JCFˆ35.4 Hz), 90.4 >t, JCFˆ6.9 Hz),
79.5 >t), 67.5 >s), 55.2 >q), 27.9 >q), 23.8 >t); HRMS >EI):
Calcd for C16H17F5N2O2 364.1210, found 364.1192.
>bs, 1H), 7.05 >d, 2H, Jˆ8.7 Hz), 6.76 >d, 2H, Jˆ8.7 Hz),
5.17 >s, 1H), 4.17 >m, 1H), 3.77±3.89 >m, 2H), 3.72 >s, 3H),
1.64 >m, 1H), 0.89 >d, 3H, Jˆ6.6 Hz), 0.82 >d, 3H,
Jˆ6.6 Hz); 19F NMR >CDCl3, 235 MHz) d 263.38 >s,
3F); 13C NMR >CDCl3, 62.8 MHz) d 164.2 >s), 157.8 >s),
3.2.5. +Z)-2-+4,5-Dihydro-1,3-oxazol-2-yl)-1-+1,1,2,2,2-
penta¯uoroethyl)-1-propenyl+4-methoxyphenyl)amine
+3g). Yellow oil, puri®ed by ¯ash chromatography on
2
143.3 >q, JCFˆ30.5 Hz), 131.8 >s), 127.3 >d), 122.9 >q,
3
1JCFˆ292.0 Hz), 113.9 >d), 84.3 >q, JCFˆ5.8 Hz), 72.1 >t),
1
deactivated >Et3N 3%) SiO2 [n-hexane±EtOAc >1:1)]; H
69.0 >d), 55.0 >q), 33.1 >d), 18.9 >q), 18.7 >q); HRMS >EI):
Calcd for C16H19F3N2O2 328.1398, found 328.1400.
NMR >CDCl3, TMS, 250 MHz) >imino tautomer) d 6.82
>d, 2H, Jˆ8.7 Hz), 6.72 >d, 2H, Jˆ8.7 Hz), 4.16 >m, 1H),
3.82 >t, 2H, Jˆ9.2 Hz), 3.70 >t, 2H, Jˆ9.2 Hz), 3.69 >s, 3H),
1.38 >d, 3H, Jˆ8.2 Hz); 19F NMR >CDCl3, 235 MHz)
>imino tautomer) d 281.42 >s, 3F), 2113.67 >s, 2F);
>enamino tautomer) d 283.03 >s, 3H), 2111.12 >s, 2H);
13C NMR >CDCl3, 62.8 MHz) >imino tautomer) d 165.0
3.2.9. +Z)-2-[+4S)-4-+tert-Butyl)-4,5-dihydro-1,3-oxazol-2-
yl]-1-tri¯uoromethyl-1-ethenyl+4-methoxyphenyl)amine
+3k). Yellow oil, puri®ed by ¯ash chromatography on
deactivated >Et3N 3%) SiO2 [n-hexane±EtOAc >4:1)];
1
a]25 ˆ172.28 >c 0.83, CDCl3); H NMR >CDCl3, TMS,
D
2
>s), 159.4 >t, JCFˆ25.7 Hz), 157.3 >s), 139.7 >s), 121.9
400 MHz) >enamino tautomer) d 10.41 >bs, 1H), 7.01 >d,
2H, Jˆ8.7 Hz), 6.75 >d, 2H, Jˆ8.7 Hz), 5.17 >s, 1H), 4.08
>m, 1H), 3.89±3.96 >m, 2H), 3.71 >s, 3H), 0.85 >s, 9H); 19F
NMR >CDCl3, 235 MHz) >enamino tautomer) d 263.36 >s,
3F); >imino tautomer) d 271.54 >s, 3F); 13C NMR >CDCl3,
100 MHz) >enamino tautomer) d 164.2 >s), 159.5 >s), 142.3
1
2
>qt, JCFˆ272.3 Hz and JCFˆ35.2 Hz), 119.8 >d), 116.0
1
2
>tq, JCFˆ260.0 Hz and JCFˆ36.8 Hz), 114.1 >d), 67.7 >t),
55.1 >q), 54.1 >t), 34.5 >d), 14.3 >q). HRMS >EI): Calcd for
C15H15F5N2O2 350.1053, found 350.1046.
2
3.2.6. +Z)-2-[+4S,5S)-4-Methoxymethyl-5-phenyl-4,5-dihy-
dro-1,3-oxazol-2-yl]-1-tri¯uoromethyl-1-ethenyl+4-meth-
>q, JCFˆ30.2 Hz), 135.4 >s), 127.4 >d), 122.2 >q,
1JCFˆ280.2 Hz), 113.9 >d), 84.5 >q, JCFˆ5.5 Hz), 75.5
3

6482
S. Fustero et al. / Tetrahedron 57 ,2001) 6475±6486
>d), 67.2 >t), 55.4 >q), 33.7 >s), 25.7 >q); HRMS >EI): Calcd
for C17H21F3N2O2 342.1555, found 342.1571.
Method B. To a solution of anhydrous zinc iodide >0.5 g,
1.56 mmol) in dry CH2Cl2 >20 mL) at 08C was added the
corresponding N-substituted b-enamino-D2-oxazolines 3
>0.52 mmol). After stirring the reaction mixture for 1 h at
08C, the reducing agent NaBH4 >0.1 g, 2.65 mmol) was
added, also at 08C. Then, the reaction was allowed to
reach room temperature, monitored by means of TLC,
quenched with saturated ammonium chloride solution
>30 mL) and extracted with dichloromethane >3£20 mL).
The combined organic extracts were washed with brine,
dried >MgSO4) and concentrated at reduced pressure to
provide the crude reaction mixture 4. Puri®cation was
carried out as indicated in each case.
3.2.10. 4-Methoxyphenyl{+Z)-2[+4R)-4-phenyl-4,5-dihy-
dro-1,3-oxazol-2-yl]-1-tri¯uoromethyl-1-ethenyl}lamine
+3l). Yellow oil, puri®ed by ¯ash chromatography on deacti-
vated >Et3N 3%) SiO2 [n-hexane±EtOAc >4:1)];
1
a]25 ˆ2331.18 >c 0.99, CDCl3); H NMR >CDCl3, TMS,
D
400 MHz) d 10.25 >bs, 1H), 7.18±7.27 >m, 5H), 7.03 >d, 2H,
Jˆ8.9 Hz), 6.73 >d, 2H, Jˆ8.9 Hz), 5.27 >s, 1H), 5.24 >t, 1H,
Jˆ8.9 Hz), 4.51 >dd, 1H, Jˆ8.8, 8.0 Hz), 3.96 >t, 1H,
Jˆ8.9 Hz), 3.69 >s, 3H); 19F NMR >CDCl3, 235 MHz) d
263.34 >s, 3F); 13C NMR >CDCl3, 100 MHz) d 165.7 >s),
2
158.0 >s), 143.9 >q, JCFˆ30.7 Hz), 142.6 >s), 131.6 >s),
128.6 >d), 127.9 >d), 127.5 >d), 126.5 >d), 120.3 >q,
3.3.1. 1-+4,5-Dihydro-1,3-oxazol-2-ylmethyl)-2,2,2-tri¯uoro-
ethyl+4-methoxyphenyl)amine +4a). Brown solid, recrys-
tallised with [n-hexane±EtOH >10:1)]; mp 82±48C; 1H
NMR >CDCl3, TMS, 250 MHz) d 6.71 >d, 2H, Jˆ8.6 Hz),
6.61 >d, 2H, Jˆ8.6 Hz), 4.17 >m, 1H), 4.01 >t, 2H,
Jˆ8.8 Hz), 3.94 >t, 2H, Jˆ8.8 Hz), 3.72 >d, 1H,
Jˆ8.9 Hz), 3.69 >s, 3H), 2.66 >dd, 1H, Jˆ14.6, 4.3 Hz),
2.47 >dd, 1H, Jˆ14.5, 9.6 Hz); 19F NMR >CDCl3,
235 MHz) d 245.71 >d, 3F, Jˆ7.2 Hz); 13C NMR
>CDCl3, 62.8 MHz) d 163.9 >s), 153.2 >s), 140.1 >s), 125.5
1JCFˆ275.0 Hz), 113.8 >d), 83.8 >q, JCFˆ6.2 Hz), 73.3 >t),
3
69.5 >d), 55.3 >q); HRMS >EI): Calcd for C19H17F3N2O2
362.1242, found 362.1239.
3.2.11. +Z)-3-Chloro+di¯uoro)methyl-2-[+4R)-4-phenyl-
4,5-dihydro-1,3-oxazol-2-yl]-1-ethenyl+4-methoxyphenyl)
amine +3m). Yellow oil, puri®ed by ¯ash chromatography
on deactivated >Et3N 3%) SiO2 [n-hexane±EtOAc >6:1)];
1
a]25 ˆ298.38 >c 0.97, CDCl3); H NMR >CDCl3, TMS,
D
1
300 MHz) >enamino tautomer) d 10.26 >bs, 1H), 7.18±
7.31 >m, 5H), 7.08 >d, 2H, Jˆ8.4 Hz), 6.74 >d, 2H,
Jˆ8.4 Hz), 5.27 >s, 1H), 5.25 >t, 1H, Jˆ8.9 Hz), 4.53 >dd,
1H, Jˆ9.0, 8.0 Hz), 3.95 >t, 1H, Jˆ8.9 Hz), 3.71 >s, 3H); 19F
NMR >CDCl3, 282 MHz) >enamino tautomer) d 250.65 >d,
1F, Jˆ183.5 Hz), 251.30 >d, 1F, Jˆ168.0 Hz); 13C NMR
>CDCl3, 75.4 MHz) d 165.6 >s), 157.9 >s), 148.4 >t,
2JCFˆ25.2 Hz), 142.4 >s), 131.3 >s), 128.8 >d), 128.5 >d),
>q, JCFˆ281.4 Hz), 115.8 >d), 114.6 >d), 67.6 >t), 55.6 >s),
54.6 >q, 2JCFˆ29.7 Hz), 54.3 >t), 28.6 >t); HRMS >EI): Calcd
for C13H15F3N2O2 288.1085, found 288.1080.
3.3.2. 2-Chloro-1-+4,5-dihydro-1,3-oxazol-2-ylmethyl)-
2,2-di¯uoroethyl+4-methoxyphenyl)amine +4b). Yellow
solid, recrystallised with [n-hexane±EtOH >10:1)]; mp
1
71±38C; H NMR >CDCl3, TMS, 250 MHz) d 6.77 >d,
1
127.4 >d), 126.4 >d), 122.5 >t, JCFˆ293.4 Hz), 113.5 >d),
2H, Jˆ8.7 Hz), 6.69 >d, 2H, Jˆ8.7 Hz), 4.36 >m, 1H),
4.22 >t, 2H, Jˆ8.7 Hz), 3.99 >t, 2H, Jˆ8.7 Hz), 3.85 >d,
1H, Jˆ8.8 Hz), 3.74 >s, 3H), 2.85 >dd, 1H, Jˆ14.6,
4.1 Hz), 2.74 >dd, 1H, Jˆ14.5, 9.6 Hz); 19F NMR
>CDCl3, 235 MHz) d 260.24 >dd, 1F, JFFˆ166.8 Hz and
JFHˆ7.8 Hz), 261.03 >dd, 1H, JFFˆ166.8 Hz and
JFHˆ7.4 Hz); 13C NMR >CDCl3, 100 MHz) d 153.2 >s),
3
82.8 >q, JCFˆ7.6 Hz), 73.2 >t), 69.3 >d), 55.1 >q); HRMS
>EI): Calcd for C19H17F2ClN2O2 380.0917, found 380.0936.
3.2.12. +Z)-2-[+3aS,8bR)-4,8b-Dihydro-3aH-indeno[2,1-d]
[1,3]oxazol-2-yl]-1-tri¯uoromethyl-1-ethenyl +4-methoxy-
phenyl)amine +3n). Yellow solid, recrystallised with [n-
hexane±EtOH >10:1)]; mp 114±58C; a]25 ˆ1453.08 >c
1
D
140.1 >s), 130.2 >s), 117.4 >t, JCFˆ289.3 Hz), 115.7 >d),
1
0.70, CDCl3); H NMR >CDCl3, TMS, 400 MHz) d 10.13
2
114.8 >d), 67.8 >t), 60.7 >t, JCFˆ26.0 Hz), 55.7 >q), 54.1
>bs, 1H), 7.19±7.37 >m, 4H), 7.03 >d, 2H, Jˆ8.9 Hz), 6.76
>d, 2H, Jˆ8.9 Hz), 5.58 >d, 1H, Jˆ8.0 Hz), 5.22 >m, 1H,
Jˆ4.5 Hz), 5.15 >s, 1H), 3.73 >s, 3H), 3.37 >dd, 1H, Jˆ17.5,
6.5 Hz), 3.22 >d, 1H, Jˆ17.5 Hz); 19F NMR >CDCl3,
282 MHz) >enamino tautomer) d 263.47 >s, 3F); >imino
tautomer) d 271.53 >s, 3H); 13C NMR >CDCl3, 100 MHz)
>t), 29.8 >t); HRMS >EI): Calcd for C13H15F2ClN2O2
304.0790, found 304.0784.
3.3.3. Cyclohexyl[1-+4,5-dihydro-1,3-oxazol-2-ylmethyl)-
2,2,2-tri¯uoroethyl]amine +4c). Colourless oil, puri®ed by
¯ash chromatography on deactivated >Et3N 3%) SiO2 [n-
2
1
d 164.7 >s), 158.0 >s), 146.9 >q, JCFˆ32.2 Hz), 142.2 >s),
hexane±EtOAc >2:1)]; H NMR >CDCl3, TMS, 400 MHz)
1
139.7 >s), 131.7 >d), 121.2 >d), 120.7 >q, JCFˆ276.9 Hz),
d 4.27±4.31 >m, 2H), 4.25 >t, 2H, Jˆ9.0 Hz), 3.51±3.57 >m,
1H), 2.41±2.67 >m, 3H), 1.62±1.84 >m, 5H), 1.60 >bs, 1H),
0.96±1.32 >m, 5H); 19F NMR >CDCl3, 235 MHz) d 276.70
>d, 3F, Jˆ7.1 Hz); 13C NMR >CDCl3, 100 MHz) d 165.1 >s),
120.8 >d), 120.2 >d), 118.2 >d), 118.0 >d), 113.8 >d), 84.1 >d),
81.5 >d), 76.2 >d), 55.4 >d), 39.5 >t); HRMS >EI): Calcd for
C20H17F3N2O2 374.1242, found 374.1235.
1
126.1 >q, JCFˆ281.1 Hz), 67.5 >t), 55.2 >t), 54.4 >q,
2JCFˆ23.2 Hz), 34.0 >d), 33.0 >t), 29.0 >t), 25.8 >t), 24.6
>t). Anal. Calcd for C12H19F3N2O: C, 54.54; H, 7.25; N,
10.60; found C, 54.28; H, 6.97; N, 10.49.
3.3. General procedure for the synthesis of N-substituted
b-amino-D2-oxazolines 4
Method A. A solution of N-substituted b-enamino-D2-
oxazolines 3 >0.3 g, 0.95 mmol) in 50 mL of MeOH was
stirred at room temperature under H2 atmosphere, in
presence of Pd/C >5% Pd) for several hours >2±24 h). The
resulting mixture was ®ltrated through a Celite pad and the
solvent removed in vacuo. Puri®cation was carried out as
indicated in each case.
3.3.4. 2-Chloro-1-+4,5-dihydro-1,3-oxazol-2-ylmethyl)-2,2-
di¯uoroethyl[+1S)-1-phenylethyl]amine +4d). Pale yellow
oil, obtained as a mixture of diastereomers that were not
separated. Data taken from the diastereomeric mixture; H
NMR >CDCl3, TMS, 400 MHz) >major diastereomer) d
7.16±7.25 >m, 5H), 3.68±4.20 >m, 5H), 3.46 >m, 1H), 2.46
1

S. Fustero et al. / Tetrahedron 57 ,2001) 6475±6486
6483
>m, 1H), 2.32 >dd, 1H, Jˆ14.5, 10.5 Hz), 2.00 >bs, 1H), 1.25
>d, 3H, Jˆ6.5 Hz); >minor diastereomer) d 7.16±7.25 >m,
5H), 3.68±4.20 >m, 5H), 3.28 >m, 1H), 2.66 >dd, 1H,
Jˆ15.0, 4.4 Hz), 2.46 >m, 1H), 2.00 >bs, 1H), 1.25 >d, 3H,
Jˆ6.5 Hz), 19F NMR >CDCl3, 235 MHz) >major diastereo-
mer) d 258.84 >dd, 1H, JFFˆ180.2 Hz and JFHˆ7.2 Hz),
259.62 >dd, 1H, JFFˆ179.4 Hz and JFHˆ7.3 Hz); >minor
diastereomer) d 257.32 >dd, 1H, JFFˆ159.8 Hz and JFHˆ
4.9 Hz), 258.75 >dd, 1H, JFFˆ160.4 Hz and JFHˆ8.5 Hz).
4-methoxymethyl-5-phenyl-4,5-dihydro-1,3-oxazol-2-
ylmethyl]ethyl}amine +4ha). Colourless oil; major
diastereomer separated by ¯ash chromatography on
deactivated >Et3N 3%) SiO2 [n-hexane±EtOAc >2:1)];
1
a]25 ˆ244.78 >c 0.96, CDCl3); H NMR >CDCl3, TMS,
D
250 MHz) d 7.10±7.23 >m, 5H), 6.70 >d, 2H, Jˆ8.4 Hz),
6.57 >d, 2H, Jˆ8.4 Hz), 5.03 >d, 1H, Jˆ7.9 Hz), 4.32 >m,
1H), 4.00 >m, 1H), 3.75 >d, 1H, Jˆ9.2 Hz), 3.66 >s, 3H),
3.37 >dd, 1H, Jˆ9.58, 4.8 Hz), 3.23 >s, 3H), 3.22 >dd, 1H,
Jˆ9.6, 6.8 Hz), 2.81 >dd, 1H, Jˆ3.9, 1.5 Hz), 2.66 >dd, 1H,
Jˆ14.6, 9.8 Hz); 19F NMR >CDCl3, 235 MHz) d 276.41 >d,
3F, Jˆ6.7 Hz); 13C NMR >CDCl3, 100 MHz) d 163.7 >s),
153.1 >s), 139.9 >s), 128.7 >d), 128.3 >d), 127.0 >q,
1JCFˆ292.3 Hz), 125.6 >d), 124.0 >s), 115.4 >d), 114.7 >d),
84.1 >d), 74.2 >d), 73.9 >t), 59.1 >q), 55.6 >q), 54.9 >q,
2JCFˆ30.0 Hz), 28.9 >t); HRMS >EI): Calcd for
C21H23F3N2O3 408.1660, found 408.1643. Anal. Calcd for
C21H23F3N2O3: C, 61.76; H, 5.68; N, 6.86; found C, 61.53;
H, 5.60; N, 6.93.
3.3.5. 1-+4,4-Dimethyl-4,5-dihydro-1,3-oxazol-2-ylmethyl)-
2,2,2-tri¯uoroethyl+4-methoxyphenyl)amine +4e). Brown
solid, recrystallised with [n-hexane±EtOH >10:1)]; mp 65±
1
68C; H NMR >CDCl3, TMS, 250 MHz) d 6.63 >d, 2H,
Jˆ8.7 Hz), 6.55 >d, 2H, Jˆ8.7 Hz), 4.08 >m, 1H), 3.61 >s,
3H), 3.59 >m, 3H), 2.64 >dd, 1H, Jˆ14.5, 4.3 Hz), 2.47 >dd,
1H, Jˆ14.5, 9.6 Hz), 1.05 >s, 3H), 1.05 >s, 3H); 19F NMR
>CDCl3, 235 MHz) d 276.56 >d, 3F, Jˆ6.4 Hz); 13C NMR
>CDCl3, 62.8 MHz) d 161.3 >s), 153.0 >s), 140.0 >s), 125.4
1
>q, JCFˆ281.1 Hz), 115.3 >d), 114.6 >d), 79.1 >t), 67.1 >s),
2
3
55.5 >q), 55.2 >q, JCFˆ30.1 Hz), 28.7 >q, JCFˆ5.7 Hz),
27.9 >q); HRMS >EI): Calcd for C15H19F3N2O2 316.1398,
found 316.1397.
3.3.9. 2-Chloro-2,2-di¯uoro-1-[+4S,5S)-4-methoxymethyl-
5-phenyl-4,5-dihydro-1,3-oxazol-2-ylmethyl]ethyl+4-
methoxyphenyl)amine +4i). Yellow oil, puri®ed by ¯ash
chromatography on deactivated >Et3N 3%) SiO2 [n-hexane±
EtOAc >3:1)]. Data taken from a diastereomeric mixture
>8:2) enriched in the major diastereomer; 1H NMR
>CDCl3, TMS, 400 MHz) d 7.130±7.23 >m, 5H), 6.62±
6.67 >m, 4H), 5.00 >d, 1H, Jˆ7.9 Hz), 4.38 >m, 1H), 4.16
>m, 1H), 3.76 >d, 1H, Jˆ9.2 Hz), 3.68 >s, 3H), 3.39 >dd, 1H,
Jˆ9.5, 4.5 Hz), 3.24 >s, 3H), 3.23 >dd, 1H, Jˆ9.5, 6.9 Hz),
2.93 >dd, 1H, Jˆ3.9, 1.6 Hz), 2.66 >dd, 1H, Jˆ14.6, 9.8 Hz);
19F NMR >CDCl3, 235 MHz) d 260.54 >m, 3F); 13C NMR
>CDCl3, 100 MHz) d 163.6 >s), 153.2 >s), 152.8 >s), 139.5
>s), 130.0 >t, 1JCFˆ290.4 Hz), 128.5 >d), 128.1 >d), 125.5 >d),
115.0 >d), 114.48 >d), 83.9 >d), 73.9 >d), 73.8 >t), 59.9 >t,
2JCFˆ30.4 Hz), 58.9 >q), 55.3 >q), 28.9 >t).
3.3.6. 1-+4,4-Dimethyl-4,5-dihydro-1,3-oxazol-2-ylmethyl)-
2,2,3,3,3-penta¯uoropropyl+4-methoxyphenyl)amine +4f).
Yellow solid, puri®ed by ¯ash chromatography on deactivated
1
>Et3N 3%) SiO2 [n-hexane±EtOAc >2:1)]; mp 80±18C; H
NMR >CDCl3, TMS, 250 MHz) d 6.66 >d, 2H, Jˆ8.6 Hz),
6.56 >d, 2H, Jˆ8.6 Hz), 4.32 >m, 1H), 3.66 >d, 1H,
Jˆ8.0 Hz), 3.64 >s, 3H), 3.58 >d, 1H, Jˆ10.8 Hz), 3.51 >d,
1H, Jˆ8.0 Hz), 2.70 >dd, 1H, Jˆ14.6, 3.5 Hz), 2.53 >dd, 1H,
Jˆ14.5, 9.7 Hz), 1.05 >s, 3H), 1.00 >s, 3H); 19F NMR >CDCl3,
235 MHz) d 281.49 >s, 3F), 2118.91 >dd, 1F, JFFˆ273.3 Hz
and JFHˆ6.5 Hz), 2127.25 >dd, 1F, JFFˆ272.8 Hz and
JFHˆ18.5 Hz); 13C NMR >CDCl3, 100 MHz) d 161.3 >s),
1
153.1 >s), 139.6 >s), 123.1 >qt, JCFˆ281.1 Hz and
1
2JCFˆ35.7 Hz), 115.2 >d), 113.1 >tq, JCFˆ259.6 Hz and
3.3.10. 4-Methoxyphenyl{2,2,2-tri¯uoro-1-+4S)-4-iso-
propyl-4,5-dihydro-1,3-oxazol-2-ylmethyl]ethyl}amine
+4j). Yellow oil, puri®ed by ¯ash chromatography on deacti-
vated >Et3N 3%) SiO2 [n-hexane±EtOAc >4:1)]. Data
obtained from a diastereomeric mixture >9:1) enriched in
the major diastereomer; 1H NMR >CDCl3, TMS,
250 MHz) d 6.70 >d, 2H, Jˆ8.5 Hz), 6.60 >d, 2H,
Jˆ8.5 Hz), 4.15 >m, 1H), 3.94 >t, 1H, Jˆ8.4 Hz), 3.78 >t,
1H, Jˆ8.4 Hz), 3.72 >t, 1H, Jˆ8.4 Hz), 3.67 >s, 3H), 2.70
>dd, 1H, Jˆ14.8, 4.2 Hz), 2.54 >dd, 1H, Jˆ14.8, 9.42 Hz),
1.54 >m, 1H, Jˆ6.6 Hz), 0.81 >d, 3H, Jˆ7.2 Hz), 0.72 >d,
3H, Jˆ7.2 Hz); 19F NMR >CDCl3, 235 MHz) >major dia-
stereomer) d 276.49 >d, 3F, Jˆ6.9 Hz); >minor diastereo-
mer) d 276.42 >d, 3F, Jˆ6.9 Hz); 13C NMR >CDCl3,
75.4 MHz) d 162.8 >s), 153.2 >s), 140.2 >s), 127.4 >q,
1JCFˆ279.3 Hz), 115.7 >d), 114.7 >d), 72.2 >d), 70.4 >t),
2JCFˆ38.7 Hz), 114.7 >d), 79.1 >t), 67.2 >s), 55.6 >q), 53.6 >t,
3
2JCFˆ21.2 Hz), 28.0 >q), 28.5 >t, JCFˆ5.5 Hz), 27.9 >q);
HRMS >EI): Calcd for C16H19F5N2O2 366.1366, found
366.1356.
3.3.7. 1-[1-+4,5-Dihydro-1,3-oxazol-2-yl)ethyl]-2,2,3,3,3-
penta¯uoropropyl+4-methoxyphenyl)amine +4g). Yellow
oil, puri®ed by ¯ash chromatography on deactivated >Et3N
3%) SiO2 [n-hexane±EtOAc >3:1)]. Data taken from a dia-
stereomeric mixture, enriched in the major diastereomer
1
>9:1); H NMR >CDCl3, TMS, 250 MHz) d 6.65 >d, 2H,
Jˆ8.8 Hz), 6.54 >d, 2H, Jˆ8.8 Hz), 4.56 >m, 1H), 3.96 >t,
2H, Jˆ8.9 Hz), 3.66 >t, 2H, Jˆ8.9 Hz), 3.61 >s, 3H), 3.39 >d,
1H, Jˆ8.8 Hz), 2.92 >m, 1H), 1.23 >d, 3H, Jˆ6.8 Hz); 19F
NMR >CDCl3, 235 MHz) d 282.34 >s, 3F), 2118.21 >dd,
1F, JFFˆ273.3 Hz and JFHˆ4.2 Hz), 2125.92 >dd, 1F,
JFFˆ296.8 Hz and JFHˆ23.5 Hz); 13C NMR >CDCl3,
62.8 MHz) d 167.7 >s), 153.0 >s), 139.9 >s), 126.5 >qt,
2
55.6 >q), 55.3 >q, JCFˆ32.3 Hz), 32.5 >t), 28.9 >d), 28.6
>d), 18.5 >q), 18.2 >q); HRMS >EI): Calcd for
C16H21F3N2O2 330.1555, found 330.1544.
2
1JCFˆ281.5 Hz and JCFˆ35.0 Hz), 115.6 >d), 114.4 >d),
1
2
96.2 >tq, JCFˆ260.2 Hz and JCFˆ38.9 Hz), 67.3 >t), 55.8
3.3.11. 1-[+4S)-4-+tert-Butyl)-4,5-dihydro-1,3-oxazol-2-
ylmethyl]-2,2,2-tri¯uoroethyl+4-methoxyphenyl)amine
+4k). Yellow oil, puri®ed by ¯ash chromatography on
deactivated >Et3N 3%) SiO2 [n-hexane±EtOAc >3:1)].
Data obtained from a diastereomeric mixture >3:1) enriched
in the major diastereomer; 1H NMR >CDCl3, TMS,
2
>t, JCFˆ27.2 Hz), 55.6 >t), 55.4 >q), 33.3 >d), 11.4 >q);
HRMS >EI): Calcd for C15H17F5N2O2 352.1210, found
352.1212.
3.3.8. 4-Methoxyphenyl{+1R)-2,2,2-tri¯uoro-1-[+4S,5S)-

6484
S. Fustero et al. / Tetrahedron 57 ,2001) 6475±6486
300 MHz) d 6.5±7.5 >m, 4H), 4.20 >m, 1H), 3.71±3.76 >m,
2H), 3.67 >s, 3H), 3.46 >m, 1H), 3.78 >t, 1H, Jˆ8.4 Hz), 2.64
>dd, 1H, Jˆ14.3, 4.1 Hz), 2.51 >dd, 1H, Jˆ14.8, 8.6 Hz),
0.81 >s, 9H); 19F NMR >CDCl3, 282 MHz) >major diastereo-
mer) d 275.86 >d, 3F, Jˆ7.2 Hz) >minor diastereomer) d
275.99 >d, 3F, Jˆ7.2 Hz); 13C NMR >CDCl3, 75.4 MHz) d
162.7 >s), 154.3 >s), 139.2 >s), 121.3 >q, 1JCFˆ280.5 Hz), 116.0
>d), 114.8 >d), 62.9 >d), 61.7 >t), 59.6 >q), 55.1 >q,
2JCFˆ30.5 Hz), 36.2 >s), 30.8 >t), 26.7 >q).
3.3.15. 1-[+3aS,8bR)-4,8b-Dihydro-3aH-indeno[2,1-d][1,3]-
oxazol-2-ylmethyl]-2,2,2-tri¯uoromethyl +4-methoxy-
phenyl)amine +4n). Data obtained from a diastereomeric
mixture >3:1) enriched in the major diastereomer; white
1
solid; H NMR >CDCl3, TMS, 300 MHz) d 6.27±7.36 >m,
8H), 4.97±5.58 >m, 2H), 4.10 >m, 1H), 3.66 >s, 3H), 3.65 >m,
1H), 3.24 >dd, 1H, Jˆ14.7, 4.1 Hz), 3.09 >dd, 1H, Jˆ14.7,
9.6 Hz), 2.62±2.68 >m, 2H); 19F NMR >CDCl3, 376 MHz)
>major diastereomer) d 276.82 >d, 3F, Jˆ8.2 Hz); >minor
diastereomer) d 276.95 >d, 3F, Jˆ8.2 Hz); 13C NMR
>CDCl3, 100 MHz) d 164.2 >s), 153.0 >s), 140.0 >s), 139.8
3.3.12. 4-Methoxyphenyl{+1R)-2,2,2-tri¯uoro-1-[+4R)-4-
phenyl-4,5-dihydro-1,3-oxazol-2-ylmethyl]ethyl}amine
+4la). Major diastereomer. White solid, separated by ¯ash
chromatography on deactivated >Et3N 3%) SiO2 [n-hexane±
1
>s), 139.3 >s), 132.2 >q, JCFˆ298.5 Hz), 128.4 >d), 127.3
>d), 126.2 >d), 115.4 >d), 114.5 >d), 74.7 >t), 69.3 >d), 60.7
>q, 2JCFˆ25.8 Hz), 55.4 >q), 55.3 >d); HRMS >EI): Calcd for
C20H19F3N2O2 380.1103, found 380.1099.
EtOAc >4:1)]; a]25 ˆ111.28 >c 0.80, CDCl3); mp 137±88C;
D
1H NMR >CDCl3, TMS, 300 MHz) d 7.00±7.18 >m, 5H),
6.71 >d, 2H, Jˆ8.8 Hz), 6.63 >d, 2H, Jˆ8.8 Hz), 5.04 >t, 1H,
Jˆ9.2 Hz), 4.40 >dd, 1H, Jˆ9.2, 8.0 Hz), 4.26 >m, 1H), 3.96
>t, 1H, Jˆ9.2 Hz), 3.72 >d, 1H, Jˆ9.2 Hz), 3.68 >s, 3H), 2.83
>dd, 1H, Jˆ14.8, 4.1 Hz), 2.64 >dd, 1H, Jˆ14.8, 9.6 Hz); 19F
NMR >CDCl3, 282 MHz) d 276.63 >d, 3F, Jˆ6.4 Hz); 13C
NMR >CDCl3, 75.4 MHz) d 164.3 >s), 153.3 >s), 141.6 >s),
140.0 >s), 128.7 >d), 127.6 >d), 126.4 >d), 120.1 >q,
1JCFˆ290.8 Hz), 115.7 >d), 114.7 >d), 74.9 >t), 69.6 >d),
3.4. Synthesis of b-aminoesters 5
A suspension of the major diastereoisomer of adduct >1)-
4la >0.15 g, 0.41 mmol) in aqueous HCl >1N, 15 mL) was
heated at re¯ux for 2 h. The solvent was removed under
reduced pressure. The residue was dissolved in equal parts
of concentrated HCl and the corresponding alcohol
>10 mL), and the solution was heated to re¯ux for 2 h.
The reaction mixture was quenched with saturated ammo-
nium chloride solution >30 mL) and extracted with dichloro-
methane >3£20 mL). The organic layers were combined,
washed with brine, and dried over sodium sulphate. After
®ltration, the solvents were removed under reduced pressure
to provide the crude reaction mixture 5. Puri®cation was
carried out as indicated in each case.
2
55.6 >q), 55.5 >q, JCFˆ30.9 Hz), 27.7 >t); HRMS >EI):
Calcd for C19H19F3N2O2 364.1398, found 364.1447. Anal.
Calcd for C19H19F3N2O2: C, 62.62; H, 5.26; N, 7.69; found
C, 62.57; H, 5.13; N 7.58.
3.3.13. 4-Methoxyphenyl{+1S)-2,2,2-tri¯uoro-1-[+4R)-4-
phenyl-4,5-dihydro-1,3-oxazol-2-ylmethyl]ethyl}amine
+4lb). Minor diastereomer. White solid, separated by ¯ash
chromatography on deactivated >Et3N 3%) SiO2 [n-hexane±
EtOAc >4:1)]; a]25 ˆ165.7 >c 1.02, CDCl3); mp 94±68C;
D
3.4.1. +R)-Methyl 4,4,4-tri¯uoro-3-+4-methoxy-phenyl-
amino)butanoate +5a). Colourless oil, puri®ed by ¯ash
chromatography on deactivated >Et3N 3%) SiO2 >n-hexane±
1H NMR >CDCl3, TMS, 300 MHz) d 7.02±7.19 >m, 5H),
6.72 >d, 2H, Jˆ8.9 Hz), 6.61 >d, 2H, Jˆ8.9 Hz), 5.06 >t, 1H,
Jˆ9.2 Hz), 4.51 >dd, 1H, Jˆ9.3, 8.0 Hz), 4.30 >m, 1H), 3.92
>t, 1H, Jˆ9.2 Hz), 3.71 >d, 1H, Jˆ9.2 Hz), 3.68 >s, 3H), 2.84
>dd, 1H, Jˆ14.8, 4.1 Hz), 2.67 >dd, 1H, Jˆ14.8, 9.6 Hz); 19F
NMR >CDCl3, 282 MHz) d 276.61 >d, 3F, Jˆ6.4 Hz); 13C
NMR >CDCl3, 75.4 MHz) d 164.3 >s), 153.3 >s), 141.6 >s),
140.0 >s), 128.7 >d), 127.6 >d), 126.4 >d), 120.1 >q,
1JCFˆ290.8 Hz), 115.7 >d), 114.7 >d), 74.9 >t), 69.6 >d),
1
EtOAc >6:1)); a]25 ˆ113.58 >c 0.42, CDCl3); H NMR
D
>CDCl3, TMS, 300 MHz) d 6.81 >d, 2H, Jˆ9.0 Hz), 6.73
>d, 2H, Jˆ9.0 Hz), 4.37 >m, 1H, Jˆ7.0 Hz), 3.76 >s, 3H),
3.70 >s, 3H), 2.83 >dd, 1H, Jˆ15.6, 4.5 Hz), 2.63 >dd, 1H,
Jˆ15.6, 8.8 Hz), 2.34 >bs, 1H); 19F NMR >CDCl3,
282.4 MHz) d 276.45 >d, 3F, Jˆ7.2 Hz); 13C NMR
>CDCl3, 100 MHz) d 170.0 >s), 155.1 >s), 139.5 >s), 125.7
2
55.6 >q), 55.5 >q, JCFˆ30.9 Hz), 27.7 >t); HRMS >EI):
1
>q, JCFˆ290.0 Hz), 116.0 >d), 114.8 >d), 55.8 >q), 54.3 >q,
Calcd for C19H19F3N2O2 364.1398, found 364.1409.
2JCFˆ28.9 Hz), 52.2 >q), 34.8 >t); HRMS >EI): Calcd for
C12H14F3NO3 277.0925, found 277.0924.
3.3.14. +1R)-2-Chloro-2,2-di¯uoro-1-[+4R)-4-phenyl-4,5-
dihydro-1,3-oxazol-2-ylmethyl]ethyl+4-methoxyphenyl)
amine +4ma). Major diastereomer. Yellow solid; separated
by ¯ash chromatography on deactivated >Et3N 3%) SiO2 [n-
3.4.2. +R)-Isopropyl 4,4,4-tri¯uoro-3-+4-methoxy-phenyl-
amino)butanoate +5b). Colourless oil, puri®ed by ¯ash
chromatography on deactivated >Et3N 3%) SiO2 >n-hexane±
hexane±EtOAc >4:1)]; a]25 ˆ133.38 >c 0.93, CDCl3); mp
D
1
146±78C; H NMR >CDCl3, TMS, 300 MHz) d 6.97±7.18
EtOAc >7:1)); a]25 ˆ219.48 >c 0.70, CDCl3) obtained from
D
1
>4l); H NMR >CDCl3, TMS, 300 MHz) d 6.71 >d, 2H,
>m, 5H), 6.71 >d, 2H, Jˆ8.8 Hz), 6.65 >d, 2H, Jˆ8.8 Hz),
5.01 >t, 1H, Jˆ9.0 Hz), 4.36 >dd, 1H, Jˆ9.0, 8.0 Hz), 4.36
>m, 1H), 3.94 >t, 1H, Jˆ9.0 Hz), 3.74 >d, 1H, Jˆ9.2 Hz),
3.68 >s, 3H), 2.93 >dd, 1H, Jˆ14.6, 4.2 Hz), 2.64 >dd, 1H,
Jˆ14.7, 9.7 Hz); 19F NMR >CDCl3, 282 MHz) d 260.54
>dd, 1F, Jˆ167.8, 7.2 Hz), 261.1 >dd, 1F, Jˆ160.3,
7.4 Hz); 13C NMR >CDCl3, 75.4 MHz) d 164.2 >s), 153.0
>s), 141.4 >s), 139.8 >s), 132.2 >t, 1JCFˆ298.5 Hz), 128.4 >d),
127.3 >d), 126.2 >d), 115.4 >d), 114.5 >d), 74.7 >t), 69.3 >d),
60.7 >t, 2JCFˆ25.8 Hz), 55.4>q), 29.8 >t); HRMS >EI): Calcd
for C19H19F2ClN2O2 380.1103, found 380.1099.
Jˆ9.0 Hz), 6.62 >d, 2H, Jˆ9.0 Hz), 4.87±4.97 >m, 1H,
Jˆ7.0 Hz), 4.22±4.32 >m, 1H), 3.67 >s, 3H), 3.37 >brd,
1H, Jˆ10.0 Hz), 2.70 >dd, 1H, Jˆ15.4, 4.4 Hz), 2.48 >dd,
1H, Jˆ15.4, 8.9 Hz), 1.13 >d, 3H, Jˆ6.2 Hz), 1.07 >d, 3H,
Jˆ6.2 Hz); 19F NMR >CDCl3, 282.4 MHz) d 276.45 >d, 3F,
Jˆ7.2 Hz); 13C NMR >CDCl3, 75 MHz) d 169.0 >s), 153.3
1
>s), 139.7 >s), 125.6 >q, JCFˆ289.3 Hz), 115.7 >d), 114.7
2
>d), 68.9 >d), 55.5 >q), 54.8 >q, JCFˆ29.7 Hz), 35.3 >t),
21.6 >q), 21.4 >q); HRMS >EI): Calcd for C14H18F3NO3
305.1238, found 305.1250.

S. Fustero et al. / Tetrahedron 57 ,2001) 6475±6486
6485
Quintana, D.; Escalante, J. Aldrichim. Acta 1994, 27, 3±11.
>b) Cole, D. C. Tetrahedron 1994, 50, 9517±9582. >c) In
Enantioselective Synthesis of b-Amino Acids; Juaristi, E.,
Ed.; VCH: New York, 1996. >d) Abdel-Magid, A. F.;
Cohen, J. H.; Maryanoff, C. A. Curr. Med. Chem. 1999, 6,
3.5. Synthesis of +R)-4,4,4-tri¯uoro-3-+4-methoxy-
phenylamino)-butan-1-ol +6)
A suspension of the major diastereoisomer of compound
>1)-4la >0.15 g, 0.41 mmol) in aqueous HCl 1N >15 mL)
was heated to re¯ux for 2 h. The solvent was removed under
reduced pressure. The residue was dissolved in dry THF
>15 mL) and LiAlH4 >0.07 g, 2 mmol) was added to the
solution at 2788C. The solution was allowed to reach
room temperature and then monitored by means of TLC.
The reaction mixture was quenched with methanol >4 mL)
and extracted with ethyl acetate >3£20 mL). The organic
layers were combined, washed with brine, and dried over
sodium sulphate. After ®ltration, the solvents were removed
under reduced pressure to provide the crude reaction
mixture 6. Puri®cation was carried out by ¯ash chroma-
tography using n-hexane±EtOAc >3:1)as eluent on silica
gel, yielding a white solid >70%).
Â
955±970. >e) Juaristi, E.; Lopez-Ruiz, H. Curr. Med. Chem.
1999, 6, 983±1004.
2. For reviews regarding the natural occurrence of b-amino
acids, see: >a) Cardillo, G.; Tomasini, C. Chem. Soc. Rev.
1996, 25, 117±128. >b) Bewley, C. A.; Faulkner, D. J.
Angew. Chem., Int. Ed. Engl. 1998, 37, 2162±2178.
>c) Scarborough, R. M. Curr. Med. Chem. 1999, 6,
971±982.
3. Several distinct total syntheses of Taxol have been disclosed.
See, for example: >a) Winkler, J. D. TetrahedronÐSymposia-
in-Print 1992, 48, 6953. >b) Nicolaou, K. C.; Guy, R. K.
Angew. Chem., Int. Ed. Engl. 1995, 34, 2079±2090. >c) For
an interesting report regarding the mode of action of Taxol
see: Chem. Eng. News April 26, 1999, 35±36 and references
cited therein.
3.5.1. +R)-4,4,4-Tri¯uoro-3-+4-methoxy-phenylamino)butyl
alcohol +6). White solid, puri®ed by ¯ash chromatography
on deactivated >Et3N 3%) SiO2 >n-hexane±EtOAc >4:1));
4. >a) Kawabata, K.; Inamoto, Y.; Sakane, K.; Iwamoto, T.;
Hashimoto, S. J. Antibiot. 1990, 43, 513±518. For another
representative examples, see: >b) Guenard, D.; Gueritte-
Voegelein, F.; Potier, P. Acc. Chem. Res. 1993, 26, 160.
>c) Bates, R. B.; Brusoe, K. G.; Burns, J. J.; Caldera, S.; Cui,
W.; Gangwar, S.; Gramme, M. R.; McClure, K. J.; Rouen, G. P.;
Schadow, H.; Stessman, C. C.; Taylor, S. R.; Vu, V. H.; Yarick,
G. V.; Zhang, J.; Pettit, G. R.; Bontems, R. J. Am. Chem. Soc.
a]25 ˆ148.88 >c 0.38, CDCl3); mp 97±98C; 1H NMR
D
>CDCl3, TMS, 300 MHz) d 6.72 >d, 2H, Jˆ9.0 Hz), 6.63
>d, 2H, Jˆ9.0 Hz), 3.99 >m, 1H), 3.79 >m, 2H), 3.68 >s, 3H),
3.60 >brd, 1H), 2.13 >m, 1H), 1.66 >m, 1H); 19F NMR
>CDCl3, 282.4 MHz) d 276.36 >d, 3F, Jˆ7.2 Hz); 13C
NMR >CDCl3, 62.8 MHz) d 153.1 >s), 140.4 >s), 126.2 >q,
1JCFˆ283.4 Hz), 115.4 >d), 114.8 >d), 58.8 >t), 55.6 >q), 54.9
Â
1997, 119, 2111±2113. >d) Fernandez, R.; Rodrõguez, J.;
Â
2
>q, JCFˆ28.9 Hz), 31.7 >t); HRMS >EI): Calcd for
Â
QuinÄoa, E.; Riguera, R.; MunÄoz, L.; Fernandez-Suarez, M.;
C11H14F3NO2 249.0976, found 249.0987.
Debitus, C. J. Am. Chem. Soc. 1996, 118, 11635±11643.
>e) Hu, T.; Panek, J. J. J. Org. Chem. 1999, 64, 3000±3001.
5. For reviews see: >a) Seebach, D.; Matthews, J. L. Chem.
Commun. 1997, 2015±2022. >b) Seebach, D.; Matthews,
J. L.; Meden, A.; Wassels, T.; Baerlocher, C.; McCusker,
L. B. Helv. Chim. Acta 1997, 80, 173±182. >c) Gellman,
S. H. Acc. Chem. Res. 1998, 31, 173±180. >d) Clark, T. D.;
Buehler, L. K.; Ghadiri, M. R. J. Am. Chem. Soc. 1998, 120,
651±656. >e) Gademann, K.; Hintermann, T.; Schreiber, J. V.
Curr. Med. Chem. 1999, 6, 905±926.
3.6. X-Ray structure analysis of 4ma
Colourless lath of 0.73£0.13£0.03 mm size, orthorhombic,
Ê
23
,
P212121, aˆ5.361>1), bˆ8.605>2), cˆ39.527>8) A,
Ê 3
Vˆ1823.5>6) A , Zˆ4, Dcˆ1.387, F>000)ˆ1192 g cm
2umaxˆ618, diffractometer Nonius CAD4, MoKa
Ê
>lˆ0.71073 A), v-scan, Tˆ273 K, 5348 re¯ections
collected of which 3918 were independent >Rintˆ0.056),
direct primary solution and re®nement on F2 using shelx
97 program,24 239 re®ned parameters, amino group hydro-
gen atom located in a difference Fourier synthesis and
re®ned with a restrained N±H bond length, other hydrogen
atoms riding, R1[I.2s>I)]ˆ0.0791, wR2 >all data)ˆ0.1774,
6. See, for example: >a) Banks, R. E.; Tatlow, J. C.; Smart, B. E.
Organo¯uorine Chemistry: Principles and Commercial
Applications; Plenum: New York, 1994. >b) Ojima, I.;
Mc Carthy, J. R.; Welch, J. T. Biomedical Frontiers of
Fluorine Chemistry; ACS Symposium Series 639; American
Chemical Society: Washington, DC, 1996. >c) Organo-
Fluorine Compounds; Houben-Weyl Methods of Organic
Chemistry, Edition E10a-c; Georg Thieme Verlag: Stuttgart,
2000, Workbench.
Ê 23
residual electron density 0.214 >20.228) eA , absolute
structure could not be determined.
7. >a) Fluorine-containing Amino Acids: Synthesis and
Properties; Kukhar, V. P., Soloshonok, V. A., Eds.; Wiley:
Chichester, 1995. >b) Enantiocontrolled Synthesis of Fluoro-
Organic Compounds; Soloshonok, V. A., Ed.; Wiley:
Chichester, UK, 1999. >c) Sutherland, A.; Willis, C. L. Nat.
Prod. Rep. 2000, 17, 621±631 and literature therein.
8. Ojima, I.; Lin, S.; Wang, T. Curr. Med. Chem. 1999, 6, 927±
954.
Acknowledgements
Â
Â
We are grateful to the Direccion General de Investigacion
Â
Â
Cientõ®ca y Tecnica and Generalitat Valenciana for ®nan-
cial support of this research >Projects PB97-0760-C02-01,
PPQ2000-0824 and GVDOC 99-22). E. S and B. P. are also
gratefully acknowledged to the Generalitat Valenciana for
Â
predoctoral fellowships. We also thank to Herminia Andres
Carpio for her assistance in experiments.
9. >a) Davis, F. A.; Reddy, R. E. Tetrahedron: Asymmetry 1994,
5, 955±960. >b) Davis, F. A.; Zhou, P.; Chen, B.-Ch. Chem.
Soc. Rev. 1998, 27, 13±18. See, also: >c) Somekh, L.;
Shanzer, A. J. Am. Chem. Soc. 1982, 104, 836±5837.
>d) Katritzky, A.; Nichols, D. A.; Qi, M. Tetrahedron Lett.
1998, 39, 7063±7066.
References
1. For recent reviews on b-amino acids, see: >a) Juaristi, E.;

6486
S. Fustero et al. / Tetrahedron 57 ,2001) 6475±6486
 Â
10. >a) Abouabdellah, A.; Begue, J.-P.; Bonnet-Delpon, D. Synlett
Â
18. >a) Fustero, S.; Pina, B.; Simon, A. Tetrahedron Lett. 1997, 38,
Â
Â
1996, 399±400. >b) Abouabdellah, A.; Begue, J.-P.; Bonnet-
Delpon, D.; Nga, T. T. J. Org. Chem. 1997, 62, 8826±8833.
See, also: >c) Guanti, G.; Ban®, L.; Narisano, E.; Scolastico,
C.; Bosone, E. Synthesis 1985, 609±611.
6771. >b) Fustero, S.; Navarro, A.; Pina, B.; Asensio, A.;
Bravo, P.; Crucianelli, M.; Volonterio, A.; Zanda, M.
Â
J. Org. Chem. 1998, 63, 6210±6219. >c) Fustero, S.; Garcõa
Â
Â
Â
de la Torre, M.; Jofre, V.; Perez Carlon, R.; Navarro, A.;
Â
Simon, A. J. Org. Chem. 1998, 63, 8825±8836.
 Â
>d) Fustero, S.; Garcõa de la Torre, M.; Pina, B.; Simo, A.
11. Uneyama, K.; Hao, J.; Amii, H. Tetrahedron Lett. 1998, 39,
4079±4082.
J. Org. Chem. 1999, 64, 5551±5556.
12. >a) Kaneko, S.; Yamazaki, T.; Kitazume, T. J. Org. Chem.
1993, 58, 2302±2312. For recent examples, see:
>b) Takaya, J.; Kagoshima, H.; Akiyama, T. Org. Lett. 2000,
2, 1577±1579.
19. For recent reviews of oxazolines, see: >a) Lutowski, K. A.;
Meyers, A. I. Asymmetric Synthesis; Morrison, J. D., Ed.;
Academic: Orlando, 1984; Vol. 3, pp 213±274. >b) Meyers,
A. I.; Gant, T. G. Tetrahedron 1994, 50, 2297±2360. See, also:
>c) Kise, N.; Ueda, N. Org. Lett. 1999, 1, 1803±1805.
>d) Shimano, M.; Meyers, A. I. J. Org. Chem. 1995, 60,
7445±7455.
13. Ojima, I.; Kato, K.; Nakahashi, K.; Fuchikami, T.; Fujita, M.
J. Org. Chem. 1989, 54, 4511±4522.
14. >a) Volonterio, A.; Bravo, P.; Zanda, M. Org. Lett. 2000, 2,
1827±1830. >b) Volonterio, A.; Bravo, P.; Moussier, N.;
Zanda, M. Tetrahedron Lett. 2000, 41, 6517±6521.
15. >a) Soloshonok, V. A.; Kirilenko, A. G.; Kukhar, V. P.;
Resnati, G. Tetrahedron Lett. 1993, 34, 3621±3624.
>b) Soloshonok, V. A.; Kirilenko, A. G.; Fokina, N. A.;
Shishkina, I. P.; Galushko, S. V.; Kukhar, V. P.; Svedas,
V. K.; Kozlova, E. V. Tetrahedron: Asymmetry 1994, 5,
1119±1126. >c) Soloshonok, V. A.; Kirilenko, A. G.;
Galushko, S. V.; Kukhar, V. P. Tetrahedron Lett. 1994, 35,
5063±5064. >d) Soloshonok, V. A.; Ono, T.; Soloshonok, I. V.
J. Org. Chem. 1997, 62, 7538±7539. >e) Soloshonok, V. A.;
Soloshonok, I. V.; Kukhar, V. P.; Svedas, V. K. J. Org. Chem.
1998, 63, 1878±1884.
Â
20. Fustero, S.; Dõaz, M. D.; Navarro, A.; Salavert, E.; Aguilar, E.
Tetrahedron Lett. 1999, 40, 1005±1008.
21. Uneyama, K.; Tamura, K.; Mizukami, H.; Maeda, K.;
Watanabe, H. J. Org. Chem. 1993, 58, 32±36.
 Â
22. >a) Fustero, S.; Navarro, A.; Dõaz, D.; Garcõa de la Torre, M.;
Â
Asensio, A.; Sanz, F.; Liu Gonzalez, M. J. Org. Chem. 1996,
Â
61, 8849±8859. >b) Fustero, S.; Dõaz, M. D.; Asensio, A.;
Navarro, A.; Kong, J.-S.; Aguilar, E. Tetrahedron 1999, 55,
2695±2712.
23. Oxazolines 1e±h were prepared following methods described
in the literature. See, for example: >a) Meyers, A. I.; Knaus,
G.; Kamata, K.; Ford, M. E. J. Am. Chem. Soc. 1976, 98, 567±
575. >b) Kamata, K.; Agata, I.; Meyers, A. I. J. Org. Chem.
1998, 63, 3113±3116. Oxazolines 1a±d were commercially
available and were used without further puri®cation: Meyers,
A. I.; Shipman, M. J. Org. Chem. 1991, 56, 7098±7102.
16. Cen, W.; Ni, Y.; Shen, Y. J. Fluorine Chem. 1995, 73, 161±
164.
Â
17. Fustero, S.; Pina, B.; Garcõa de la Torre, M.; Navarro, A.;
Â
Ramõrez de Arellano, C.; Simon, A. Org. Lett. 1999, 1,
Â
È
24. Sheldrick, G. M. shelx-97, University of Gottingen, 1997.
977±980.