A new and expeditious strategy for the synthesis of β-amino acids from Δ2-oxazolines

Article abstract of DOI:10.1016/S0040-4020(00)01056-5

A new, mild two-step synthesis of racemic β-amino acids starting from 2-alkyl-Δ²-oxazolines is described. The process implies the initial formation of masked N-substituted or N-unsubstituted β-enamino acid derivatives followed by chemoselective reduction of the enamino moiety. The process takes place with high yields, total chemoselectivity and moderate diastereoselectivity.

Full text of DOI:10.1016/S0040-4020(00)01056-5

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 703±712
A new and expeditious strategy for the synthesis of b-amino acids
from D2-oxazolines
a,p
a
a
a
a
Santos Fustero, M Dolores Dõaz, Antonio Navarro, Esther Salavert and Enrique Aguilar
b
Â
a
   Â
Departamento de Quõmica Organica, Facultad de Farmacia, Avda. Vicente Andres Estelles s/n, Universidad de Valencia,
46100 Burjassot, Valencia, Spain
Â
b
    Â
Departamento de Quõmica Organica e Inorganica, Facultad de Quõmica, Avda. Julian Claverõa s/n, Universidad de Oviedo, 33006,
Oviedo, Spain
Received 10 July 2000; revised 30 October 2000; accepted 8 November 2000
AbstractÐA new, mild two-step synthesis of racemic b-amino acids starting from 2-alkyl-D2-oxazolines is described. The process implies
the initial formation of masked N-substituted or N-unsubstituted b-enamino acid derivatives followed by chemoselective reduction of the
enamino moiety. The process takes place with high yields, total chemoselectivity and moderate diastereoselectivity. q 2001 Elsevier
Science Ltd. All rights reserved.
1. Introduction
ample role in several aspects of synthetic organic chemistry,
namely their utility as chiral auxiliaries, chiral ligands,
chiral building blocks and intermediates in the synthesis
of b-lactams.7
Recently, increasing attention has been focused on b-amino
acids, which are 1,3-difunctionalised compounds. This is
partly due to the fact that b-peptides, which consist entirely
of b-amino acids rather than a-amino acids, are an
emerging class of unnatural biopolymers with interesting
secondary structures.1,2 It has also been demonstrated that
b-peptides are resistant to the action of proteases,3 which
bodes well for medicinal purposes. In addition, the isolation
of naturally occurring molecules containing b-amino acids
is also growing. Many cyclic and non-cyclic peptides with
important pharmacological properties have been isolated
from marine organisms or from plants, and aromatic
and aliphatic b-amino acids, as well as proteinogenic
amino acids and some unusual acid moieties such as
hydroxyacids, have been found to be components of these
molecules.4
As a consequence, a variety of procedures for preparing
b-amino acids has been described,4a,8 and can be classi®ed
into the following categories: (i) conjugate addition of
primary or secondary amines or hydroxyl amines to a,b-
unsaturated esters or nitriles,9 (ii) addition of C-nucleophiles
to imines,10 (iii) alkylation of b-amino ester or amide
enolates,11 (iv) homologation of a-amino acids,12 (v) trans-
formations of aspartic acid derivatives,13 including methods
that apply Seebach's self-reproduction of chirality
concept,14 (vi) chemoenzymatic methods15 and (vii)
selective reduction of 3-aminoacrylic acid derivatives.16,17
Among all of these procedures, the chemoselective reduc-
tion of the enamino moiety in b-enamino acid derivatives
has received much less attention due, perhaps, to the high
reactivity of the ester function towards a great number of
reducing agents, which thus diminishes the regioselectivity
of the process.
In some cases, the substitution of a-amino acids for their
b-isomers in biologically active peptides involves an
increase in the activity and enzymatic stability of the result-
ing peptide.5 However, together with the widely recognised
biological activity as part of peptidic chains, terpenes,
alkaloids, macrolides and b-lactam antibiotics, several
b-amino acids also show interesting pharmacological
properties by themselves.6 A third reason for the increased
development of b-amino acid chemistry is the result of their
A simple way to overcome this problem would be to block
this functionality through the use of protecting groups.
Heterocyclic systems such as D2-thiazolines, D2-imidazo-
lines and especially D2-oxazolines have shown great
synthetic potential as both carboxylic acid-protecting
groups, chiral auxiliaries in asymmetric reactions and as
chiral ligands in metal-catalysed asymmetric synthesis.18,19
The reaction of commercially available 2-alkyl-2-oxazo-
lines 1 with a variety of nitriles 220 or with imidoyl chlorides
321 has allowed us to devise two different approaches to
Keywords: amino acids and derivatives; oxazolines; reduction; regio-
selection; stereoselection.
* Corresponding author. Tel.: 134-96-386-4279; fax: 134-96-386-4939;
e-mail: santos.fustero@uv.es
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01056-5

704
S. Fustero et al. / Tetrahedron 57 (2001) 703±712
2. Results and discussion
The use of dissolving metals is one of the easiest methods to
achieve the reduction of a large number of organic
compounds. Since the sodium/iso-propanol system has
been successfully used to perform the reduction of
related systems such as 4-amino-1-aza-1,3-butadienes24 or
b-enaminoesters,16a we decided to initiate our research
by testing it in compounds 4. Thus, when C-protected
b-enamino acids 4 were treated with an excess of sodium
in THF as the solvent and iso-propanol as the proton source
at 08C and the reaction was allowed to reach room tempera-
ture, the corresponding C-protected b-amino acids 5 were
obtained, after work-up, in the yields reported in Table 1
(Scheme 2). The reaction was ®nished in under two hours
for N-substituted 4 (R1±H) and in less than six hours for
N-unsubstituted 4 (R1ˆH). At longer reaction times, intract-
able mixtures of compounds were obtained as the result of
product decomposition; however, the reaction was chemo-
selective as no reduction of the oxazoline moiety was
Scheme 1.
masked b-dehydroamino acids 4, thus extending the
reactivity of 2-alkyl-2-oxazolines (Scheme 1). It should
also be pointed out that while this manuscript was under
preparation, a ®rst report regarding the application of
these new derivatives 4 as chiral ligands for asymmetric
catalysis was published.22 In the present paper, we disclose
our results regarding the development of a simple two-step
strategy for obtaining racemic b-amino acids from masked
b-enamino acids 4 through chemoselective reduction of the
enamino moiety and deprotection of the carboxylic
function.23
1
detected in the H NMR spectrum of the crude residue.
Compounds 5 were usually obtained in high yields, inde-
pendently of the substituents in the oxazoline moiety. The
only requirement was that the R2 substituent be an aromatic
or heteroaromatic group; when R2 was an aliphatic
Table 1. Synthesis of b-amino acid derivatives 5
Entry
1a
Sm
R1
R2
R3
Product
Syn/antib
Yield (%)c,d
One-pot yield (%)c
1
2
3
4
5
6
7
8
1a
1a
1a
1b
1a
1a
1a
1b
1c
1c
1c
1c
1a
1d
1a
1a
1a
1a
1b
1b
1b
1a
1b
1a
1a
1a
1b
1c
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
H
H
H
H
Ph
Ph
p-Me±C6H4
p-MeO±C6H4
Ph
Ph
t-Bu
p-Me±C6H4
p-MeO±C6H4
Ph
p-Me±C6H4
p-MeO±C6H4
2-Furyl
p-Me±C6H4
p-Me±C6H4
Ph
Ph
H
H
H
Me
H
5a
5b
5c
95 (82)
90 (85)
87 (88)
75e
82
96
5d
5e
30/70
99
75
p-MeO±C6H4
H
H
H
H
H
H
H
H
c-C6H11
p-MeO±C6H4
(^)-Ph(Me)CH
Ph
Ph
(^)-Ph(Me)CH
Ph
p-Me-C6H4
p-Me±C6H4
H
p-MeO±C6H4
Ph-CO±
Ph-CO±
Ph-CO±
H
5fh
5g
5h
5i
Me
Me
H
H
H
H
Allyl
H
H
H
18/82
30/70
90e (80)e
95e
72
90e (85)e,f
9
88
97
77
92
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
5j
5k
5l
5m
5n
5o
5p
5q
5r
92
93
83
96e
37/63
83g
98
99
Ph
p-MeO±C6H4
Ph
Ph
H
H
80g
98
4s
4t
Me
Me
Me
H
Me
H
H
H
Me
H
5s
5t
17/83
18/82
23/77
88e
96i
4u
4v
4w
4x
4y
5a
anti-5d
5i
p-MeO±C6H4
5u
5vh
5wh
91e
85
t-Bu
t-Bu
2-Pyridyl
CF3
Ph
Ph
90e
j
-
-
j
5x
anti-5y
5z
98k
60k
75k
Ph
a Structure of the oxazoline moiety: 1a, 2-methyl-2-oxazoline; 1b, 2-ethyl-2-oxazoline; 1c, 2,4,4-trimethyl-2-oxazoline; 1d, (4S,5S)-4-methoxymethyl-2-
methyl-5-phenyl-2-oxazoline.
1
b Calculated from crude mixture by H NMR (300 MHz).
c Yield of crude product (not optimised).
d In brackets, yield of crude product when using t-BuOH as proton source.
e Yield of the mixture of diastereomers.
f Crude yield starting from 2-ethyl-2-oxazoline 1b (three steps).
g Yield of a mixture of diastereomers (1:1) (not separated).
h NaBH4/MeOH was used as reducing agent.
i Yield of a mixture of 4 diastereomers (1:3:1:3) (not separated).
j A complex mixture of products was obtained.
k Yield of isolated product after recrystallization.

S. Fustero et al. / Tetrahedron 57 (2001) 703±712
705
Scheme 2.
substituent, complex mixtures were obtained and the desired
product 5, although detected, could not be isolated. Also for
the ¯uorinated derivative 4y and for 4x (R2ˆ2-pyridyl) a
complex mixture of unde®ned products was obtained as a
result, in the latter case, of partial and/or total reduction of
the heteroaromatic substituent (entries 24, 25, Table 1).
distillation, ¯ash chromatography (silica gel, alumina,
¯orisil) or medium-pressure liquid chromatography
(MPLC), as had been previously observed for related
N-unsubstituted b-amino ketones.24,25 For this reason and
bearing in mind that N-substituted oxazoline-protected
b-amino acids 5 (R1±H) are more stable, several deriva-
tives 5 (R1ˆH) were benzoylated through reaction with
PhCOCl/Et3N/DMAP to afford N-benzoylated oxazoline-
protected b-amino acids 5x±z (R1ˆCOPh) (entries 26±28,
Table 1, Scheme 2).
N-Unsubstituted b-amino acid derivatives 5 (R1ˆH) are
very polar and water soluble; therefore, in order to avoid a
decrease of the reaction yield, the quenching of the reaction
mixture was performed with the minimum (stoichiometric)
amount of a NH4Cl saturated aqueous solution.
Closely related conditions (Na/NH3(l)/t-BuOH) were
recently described by Kishi26 and we decided to test them
in an attempt to improve the diastereoselectivity of the
reduction process, as the reaction proceeded at lower
temperature (2458C). However, in all cases a mixture of
the starting material 4, the desired reduced compound 5 and
another product 6, resulting from the opening of the oxazo-
line portion, were obtained in variable proportions. If the
reaction was allowed to continue, the amount of 6 was
increased, and after 30 min the crude reaction was almost
exclusively compound 6 (Scheme 3).
When R3±H the chemoselective reduction of the enaminic
double bond generated mixtures of syn/anti diastereomers in
a moderate and variable (1:1.3 to 1:4.8) ratio, as a new
stereocenter was created. Attempts to improve the diastereo-
selectivity by decreasing the reaction temperature, changing
the reaction time, or using another proton source such as
tert-butanol were completely ineffective. The identi®cation
1
of compounds 5 was carried out by means of H and 13C
NMR and HRMS. The value of the coupling constants, as
well as the chemical shift for the H in a position to the
amino group, was decisive in the elucidation of syn/anti
diastereomers. In related systems, the coupling constant is
bigger and the chemical shift located at higher ®eld for
the anti than for the syn diastereomer.24,25 In our case, the
chemical shift and the coupling constant of the H a to the
NH2 group in, for example, compound 5d are 3.88 ppm and
9.6 Hz, respectively, for the anti isomer and 4.15 ppm and
5.2 Hz for the syn isomer.
Other reducing agents such as complex metal hydrides (i.e.
NaBH4, NaBH3CN, LiAlH4) under different conditions
(NaBH4/I2,27
NaBH4/MsOH,28
NaBH4/AcOH,16a
NaBH3CN/
NaBH3CN/MeOH,29
NaBH3CN/AcOH,30
CF3CO2H31) have also been tested, but they were inef®cient,
yielding either a complex mixture of products or the
recovered starting material. One exception to this general
behaviour is the case of b-tert-leucine derivatives 4f,v,w.
These compounds generally appear as imino tautomers,
because of steric effects between the t-butyl and aryl
(vR1) groups;21 consequently, they can also be reduced
by other agents such as complex metal hydrides (Scheme
4). Thus, when 4f,v,w were allowed to react with NaBH4 in
a THF/MeOH mixture (3:1) at 258C, the corresponding
b-amino derivatives 5f,v,w were synthesised in high
yields (entries 6, 22, 23, Table 1 and Scheme 4). In the
When chiral non-racemic compound 4n, which bears
the chirality in the oxazoline portion, was treated with
Na/i-PrOH in the conditions described, an equimolecular
mixture of diastereomers was obtained. In this case neither
diastereomer could be separated and no asymmetric
induction was observed.
In most instances the crude product showed satisfactory
spectroscopic data and could be used in the following step
without puri®cation. When necessary, the puri®cation of
compounds 5 was carried out either by means of ¯ash
chromatography or recrystallisation. However, several
N-unsubstituted oxazoline-protected b-amino acids
5
(R1ˆH), isolated as pale yellow oils, were too unstable for
Scheme 3.

706
S. Fustero et al. / Tetrahedron 57 (2001) 703±712
case with oxazoline derivatives 4 (vide supra), while the use
of dissolving metals (Na/i-PrOH) in conditions identical to
those used for oxazoline derivatives 4 resulted in the
complete reduction of the unsaturated system, with con-
comitant opening of the thiazoline ring to yield compound
8a (Scheme 5). This disappointing result, although not
totally unexpected, led us to focus our research on the
reduction of compounds 4.
Scheme 4.
The last step in the preparation of b-amino acids 9 involved
the deprotection of the carboxylic function of compounds 5
and could be carried out conveniently by means of acidic
hydrolysis. Thus, treatment of b-amino oxazolines 5 in
re¯uxing 3N HCl for 2±3 h yielded the desired b-amino
acids 9 along with the recovery of b-amino alcohols 10.
Finally, isolation and puri®cation of b-amino acids 9 were
achieved by means of ¯ash chromatography and recrystalli-
sation for N-substituted b-amino acids 9 (R1±H) and by
means of ion-exchange chromatography (Dowex-50, H1
form) for N-unsubstituted b-amino acids 9 (R1ˆH), to
afford the corresponding derivatives in moderate to good
yields (Table 2, Scheme 6).
Scheme 5.
case of a-substituted derivatives such as 4w, a separable
mixture of syn/anti (1:3) diastereomers 5w was obtained
(entry 23, Table 1). The preference for the major diastereo-
isomer anti-5w can be easily explained if it is assumed that,
in a Felkin±Ahn model, the hydride attacks the imino
carbon from the opposite side of the a-methyl group.
It should also be pointed out that, besides the option of being
transformed into b-amino acids, several C-oxazoline
protected b-amino acids 5 present latent functionality that
can be developed to convert them into interesting organic
compounds. Thus, for example, compounds 5 in which
R2ˆ2-Furyl or p-MeO±C6H4 are potential precursors of
a-amino acids (in fact, they can be regarded as synthons
of aspartic acid) when standard procedures are used to trans-
form the R2 group into a carboxyl group.33 Moreover, in
these cases both carboxylic functions are masked behind
orthogonal protecting groups.
It is worth noting that N-unsubstituted C-protected b-amino
acids 5 (R1ˆH) can also be obtained in a one-pot procedure
starting from 2-alkyl-2-oxazolines 1 (Scheme 2). This
reaction involves three or four steps, depending on whether
the alkylation is carried out or not, and is convenient since
the isolation of intermediates 4 is not necessary, thus saving
time and material. Furthermore, in many cases, this one-pot
reaction provides higher yields than the stepwise sequence
(entries 2, 9, 10, 12, Table 1) making it the method of choice
for preparing derivatives 5 (R1ˆH).
In summary, we have described our initial studies of a
simple and convenient procedure for the regioselective
reduction of racemic C-protected b-enamino acids 5. The
iminic or enaminic nature of compounds 5 determines the
reducing agent to be employed; thus, enaminic tautomers 5
can be reduced by dissolving metals (Na/i-PrOH) while
complex metal hydrides (NaBH4) can be used for iminic
As the thiazoline ring has also been used as a protective
group for the carboxylic function,32 we analysed the reduc-
tion of thiazoline-protected b-enamino derivatives 7. The
treatment of 7 (for example 7a) with complex metal
hydrides (LiAlH4, NaBH4) was inef®cient as had been the
Table 2. Synthesis of b-amino acids 9
Entry
Sm
R1
R2
R3
Product
Yield (%)a
1
2
3
4
5
6
5a
5b
5c
anti-5d
5e
H
H
H
H
Ph
Ph
p-Me±C6H4
p-MeO±C6H4
Ph
Ph
t-Bu
H
H
H
Me
H
9a
9b
9c
anti-9d
9e
90
73
51
46
90
88
5f
p-MeO±C6H4
H
9f
a Isolated yield after puri®cation.
Scheme 6.

S. Fustero et al. / Tetrahedron 57 (2001) 703±712
707
tautomers 5. N-Unsubstituted compounds 5 (R1ˆH) can
also be accessed through a facile one-pot procedure from
oxazolines 1 in high yields, thus avoiding the isolation of
intermediates 4. Finally, standard deprotection of the
carboxylic function yields the desired b-amino acids 9.
Further work to improve the diastereoselectivity in the
reduction step, either by choosing a different chiral auxiliary
in the oxazoline portion or by investigating other reduction
conditions (i.e. catalytic hydrogenation) is in progress and
will be reported at another time.
166.6 (s), 144.8 (s), 128.5 (d), 127.3 (d), 126.1 (d), 67.1
(t), 54.3 (t), 53.1 (d), 37.9 (t); HRMS (EI): calcd for
C11H14N2O 190.1106, found 190.1111.
3.2.3. 2-(2-Amino-2-p-tolyl)ethyl-2-oxazoline (5b). White
1
solid. Mp 47±498C; H NMR (CDCl3, TMS, 300 MHz) d
7.25 (d, 2H, Jˆ8.0 Hz), 7.15 (d, 2H, Jˆ8.0 Hz), 4.36 (t, 1H,
Jˆ6.4 Hz), 4.26 (t, 2H, Jˆ9.1 Hz), 3.84 (t, 2H, Jˆ 9.1 Hz),
2.59 (dd, 2H, Jˆ7.3 and 6.4 Hz), 2.56 (s, 3H), 2.20±2.00
(bs, 2H); 13C NMR (CDCl3, 75.4 MHz) d 166.4 (s), 141.7
(s), 136.6 (s), 128.9 (d), 125.8 (d), 66.8 (t), 54.0 (t), 52.5 (d),
37.7 (t), 20.7 (q); HRMS (EI): calcd for C12H16N2O
204.1262, found 204.1267.
3. Experimental
3.1. General
3.2.4. 2-(2-Amino-2-p-methoxyphenyl)ethyl-2-oxazoline
(5c). Pale yellow oil; H NMR (CDCl3, TMS, 250 MHz)
1
THF was distilled under argon from sodium/benzophenone
ketyl as drying agent. Diisopropylamine, used to generate
LDA, was re¯uxed over KOH, distilled, and stored
d 7.30 (d, 2H, Jˆ9.1 Hz), 6.85 (d, 2H, Jˆ9.1 Hz), 4.34 (t,
1H, Jˆ6.9 Hz), 4.22 (t, 2H, Jˆ9.5 Hz), 3.81 (t, 2H, Jˆ
9.5 Hz), 3.80 (s, 3H), 2.57 (dd, 2H, Jˆ7.6, 6.9 Hz), 2.00
(bs, 2H); 13C NMR (CDCl3, 62.8 MHz) d 166.6 (s), 158.7
(s), 136.9 (s), 127.1 (d), 113.8 (d), 67.0 (t), 55.2 (q), 54.2 (t),
52.4 (d), 38.0 (t); HRMS (EI): calcd for C12H16N2O2
220.1213, found 220.1211. Anal. calcd for C12H16N2O2:
C 65.43, H 7.32, N 12.72; found: C 65.28, H 7.40, N
12.51.
Ê
under argon in the presence of 4 A molecular sieves at
48C. i-PrOH and t-BuOH were dried by re¯uxing them
over magnesium activated with iodine and distilled.
Solvents used in extractions, recrystallisations, and in
chromatographic columns were distilled prior to use.
b-Enamino acid derivatives 4 and 7 were prepared as
described.20,21 All other reagents were commercially avail-
able and were used without further puri®cation. Complete
descriptions of the equipment and analytical methods used
for the synthesis and characterisation of the described
compounds have been previously reported.20b,21
3.2.5. 2-(2-Amino-1-methyl-2-phenyl)ethyl-2-oxazoline
(5d). Pale yellow oil, obtained as a syn/anti mixture of
diastereoisomers. Data for the minor isomer were obtained
from a diastereomerically enriched mixture. HRMS (EI):
calcd for C12H16N2O 204.1262, found 204.1262.
3.2. Synthesis of D2-oxazoline protected b-amino acids 5.
Two different methods (A and B) were employed
depending on which tautomeric form (enamine or imine)
was present in the starting material.
3.2.6. (1Sp,2Rp)-2-(2-Amino-1-methyl-2-phenyl)ethyl-2-
oxazoline (anti-5d). H NMR (CDCl3,TMS, 250 MHz) d
7.36±7.21 (m, 5H), 4.10 (t, 2H, Jˆ9.2 Hz), 3.88 (d, 1H,
Jˆ9.6 Hz), 3.71 (t, 2H, Jˆ9.2 Hz), 2.71 (m, 1H), 2.00 (bs,
2H), 0.84 (d, 3H, Jˆ7.3 Hz); 13C NMR (CDCl3, 62.8 MHz)
d 170.5 (s), 143.7 (s), 128.4 (d), 127.3 (d), 126.5 (d), 66.9
(t), 59.2 (d), 54.1 (t), 41.7 (d), 15.7 (q).
1
3.2.1. Method A: Reduction of D2-oxazoline protected
b-enamino acids 4. Isopropanol (3 mL, via syringe) and
Na (excess) in small portions were successively added
under inert atmosphere to a solution of the starting material
4 (20.0 mmol) in dry THF (10 mL) at 08C. The reaction
mixture was stirred and allowed to reach room temperature.
When TLC monitoring indicated complete disappearance of
the starting material (2±6 h), the excess of Na was removed
and a saturated aqueous solution of NH4Cl (4±5 mL) was
added. [For N-unsubstituted b-amino acid derivatives
(R1ˆH) a minimum (stoichiometric) amount of NH4Cl
was added.] The reaction mixture was extracted with
dichloromethane (3£15 mL); the combined organic layer
was dried over MgSO4, ®ltered, and solvents were evapo-
rated under reduced pressure to give a residue that, in most
cases, was spectroscopically pure and could be used without
further puri®cation. When necessary, puri®cation was
carried out either by means of ¯ash chromatography over
SiO2 or by recrystallisation, if solid, to give the correspond-
ing D2-oxazoline protected b-aminoacid 5 in the yield
reported in Table 1.
3.2.7. (1Sp,2Sp)-2-(2-Amino-1-methyl-2-phenyl)ethyl-2-
oxazoline (syn-5d). H NMR (CDCl3, TMS, 250 MHz) d
1
7.36±7.21 (m, 5H), 4.15 (d, 1H, Jˆ5.2 Hz), 3.98 (t, 2H,
Jˆ9.2 Hz), 3.59 (t, 2H, Jˆ9.2 Hz), 2.71 (m, 1H), 2.00 (bs,
2H), 1.10 (d, 3H, Jˆ7.3 Hz); 13C NMR (CDCl3, 62.8 MHz)
d 170.5 (s), 143.7 (s), 128.4 (d), 128.1 (d), 127.0 (d), 66.9
(t), 57.3 (d), 54.1 (t), 41.0 (d), 11.9 (q).
3.2.8. 2-(2-Anilino-2-phenyl)ethyl-2-oxazoline (5e). White
solid. Mp 137±98C; H NMR (CDCl3, TMS, 250 MHz) d
1
7.41±7.05 (m, 7H), 6.68±6.51 (m, 3H), 4.72 (bs, 1H), 4.70
(m, 1H), 4.20 (t, 2H, Jˆ9.5 Hz), 3.81 (t, 2H, Jˆ9.5 Hz), 2.75
(m, 2H); 13C NMR (CDCl3, 62.8 MHz) d 165.5 (s), 147.3 (s),
142.6 (s), 129.0 (d), 128.7 (d), 127.3 (d), 126.1 (d), 117.5 (d),
113.5 (d), 67.4 (t), 55.3 (t), 54.3 (d), 36.8 (t); HRMS (EI):
calcd for C17H18N2O 266.1419, found 266.1426.
3.2.9. (1Sp,2Rp)-2-(2-Amino-1-methyl-2-p-tolyl)ethyl-2-
oxazoline (anti-5g). White solid. Mp 92±48C; H NMR
1
3.2.2.
2-(2-Amino-2-phenyl)ethyl-2-oxazoline
(5a).
Colourless oil; 1H NMR (CDCl3, TMS, 250 MHz) d
7.40±7.20 (m, 5H), 4.35 (t, 1H, Jˆ7.4 Hz), 4.17 (t, 2H,
Jˆ9.2 Hz), 3.79 (t, 2H, Jˆ9.2 Hz), 2.54 (dd, 2H, Jˆ7.4,
6.2 Hz), 1.80 (bs, 2H); 13C NMR (CDCl3, 62.8 MHz) d
(CDCl3, TMS, 250 MHz) d 7.30±7.10 (m, 4H), 4.27 (t,
2H, Jˆ9.6 Hz), 4.00 (d, 1H, Jˆ9.4 Hz), 3.88 (t, 2H,
Jˆ9.6 Hz), 2.69 (m, 1H), 2.34 (s, 3H), 1.75 (bs, 2H), 0.95
(d, 3H, Jˆ7.0 Hz); 13C NMR (CDCl3, 62.8 MHz) d 170.0

708
S. Fustero et al. / Tetrahedron 57 (2001) 703±712
(s), 140.8 (s), 137.1 (s), 129.2 (d), 127.0 (d), 67.1 (t), 59.0
(d), 54.2 (t), 41.8 (d), 21.1 (q), 15.9 (q); HRMS (EI): calcd
for C13H18N2O 218.1413, found 218.1419. Anal. calcd for
C13H18N2O: C 71.53, H 8.31, N 12.83; found: C 71.39, H
8.20, N 12.86.
3.2.16. 2-[2-Amino-2-(2-furyl)]ethyl-4,4-dimethyl-2-oxa-
zoline (5l). Pale yellow oil; 1H NMR (CDCl3, TMS,
250 MHz) d 7.25 (d, 1H, Jˆ1.8 Hz), 6.20 (dd, 1H, Jˆ2.9,
1.8 Hz), 6.09 (d, 1H, Jˆ2.9 Hz), 4.32 (dd, 1H, Jˆ8.5,
5.0 Hz), 3.82 (s, 2H), 2.65 (dd, 1H, Jˆ8.5, 5.0 Hz), 2.52
(dd, 1H, Jˆ8.5, 8.5 Hz), 2.00 (bs, 2H), 1.18 (s, 3H), 1.17
(s, 3H); 13C NMR (CDCl3, 62.8 MHz) d 163.4 (s), 157.2 (s),
141.5 (d), 109.9 (d), 104.6 (d), 78.8 (t), 67.0 (s), 47.2 (d),
35.6 (t), 28.3 (q). Anal. calcd for C11H16N2O2: C 63.46, H
7.69, N 13.46; found: C 63.38, H 7.80, N 13.37.
3.2.10. 2-[2-Amino-2-(p-methoxyphenyl)-1-methyl]ethyl-
2-oxazoline (5h). Pale yellow oil, obtained as a mixture of
diastereoisomers that were not separated. Data for each
diastereoisomer were obtained from the diastereomeric
mixture. HRMS (CI): calcd for C13H16NO2 (M1112NH3)
218.1180, found 218.1181.
3.2.17. 2-(1-Amino-1-p-tolyl)but-3-en-1-yl-2-oxazoline (5m).
Pale yellow oil; diastereoisomers not separated; data
obtained from a 37:63 mixture of diastereoisomers.
HRMS (FAB): calcd for C15H20N2O (M111) 245.1654,
found 245.1657.
3.2.11. (1Sp,2Rp)-2-(2-Amino-2-p-methoxyphenyl-1-methyl)-
ethyl-2-oxazoline (anti-5h). 1H NMR (CDCl3, TMS,
400 MHz) d 7.20 (d, 2H, Jˆ6.8 Hz), 6.82 (d, 2H,
Jˆ6.8 Hz), 4.25 (t, 2H, Jˆ9.2 Hz), 3.95 (d, 1H, Jˆ
9.2 Hz), 3.88 (t, 2H, Jˆ9.2 Hz), 3.76 (s, 3H), 2.71 (m, 1H),
2.00 (bs, 2H), 0.90 (d, 3H, Jˆ7.2 Hz); 13C NMR (CDCl3,
100 MHz) d 170.7 (s), 158.8 (s), 135.7 (s), 128.0 (d), 113.8
(d), 67.0 (t), 58.6 (d), 55.2 (q), 54.2 (t), 41.9 (d), 15.8 (q).
3.2.18. (1Sp,2Rp)-2-(1-Amino-1-p-tolyl)but-3-en-1-yl-2-
oxazoline (anti-5m). Major diastereoisomer; 1H NMR
(CDCl3, TMS, 250 MHz) d 7.20±7.00 (m, 4H), 5.60 (m,
1H), 4.88 (m, 2H), 4.12 (t, 2H, Jˆ9.2 Hz), 3.95 (d, 1H,
Jˆ9.6 Hz), 3.80 (t, 2H, Jˆ9.2 Hz), 2.65 (m, 1H), 2.23 (s,
3H), 2.00 (m, 2H), 1.80 (bs, 2H); 13C NMR (CDCl3,
62.8 MHz) d 168.9 (s), 140.6 (s), 137.1 (s), 135.1 (d),
129.2 (d), 126.8 (d), 116.5 (t), 66.9 (d), 57.3 (t), 54.1 (t),
47.3 (t), 34.6 (d), 21.0 (q).
3.2.12. (1Sp,2Sp)-2-(2-Amino-2-p-methoxyphenyl-1-methyl)-
ethyl-2-oxazoline (syn-5h). 1H NMR (CDCl3, TMS,
400 MHz) d 7.20 (d, 2H, Jˆ6.8 Hz), 6.82 (d, 2H,
Jˆ6.8 Hz), 4.17 (t, 2H, Jˆ9.2 Hz), 3.95 (d, 1H, Jˆ
9.2 Hz), 3.75 (t, 2H, Jˆ9.2 Hz), 3.76 (s, 3H, 2.73 (m, 1H),
2.00 (bs, 2H), 1.12 (d, 3H, Jˆ7.2 Hz); 13C NMR (CDCl3,
100 MHz) d 170.7 (s), 158.8 (s), 135.7 (s), 127.6 (d), 113.5
(d), 75.0 (t), 58.6 (d), 56.9 (q), 54.1 (t), 41.2 (d), 12.2 (q).
3.2.19. (1Sp,2Sp)-2-(1-Amino-1-p-tolyl)but-3-en-1-yl-2-
oxazoline (syn-5m). Minor diastereoisomer; 1H NMR
(CDCl3, TMS, 250 MHz) d 7.20±7.00 (m, 4H), 5.70 (m,
1H), 5.00 (m, 2H), 4.12 (m, 3H), 3.60 (t, 2H, Jˆ9.2 Hz),
2.65 (m, 1H), 2.25 (s, 3H), 2.05 (m, 2H), 1.80 (bs, 2H); 13C
NMR (CDCl3, 62.8 MHz) d 168.5 (s), 140.2 (s), 136.7 (s),
135.9 (d), 128.8 (d), 126.5 (d), 116.3 (t), 66.8 (d), 57.1 (t),
53.9 (t), 46.9 (t), 32.5 (d), 21.0 (q).
3.2.13. 2-(2-Amino-2-phenyl)ethyl-4,4-dimethyl-2-oxa-
zoline (5i). Colourless oil; 1H NMR (CDCl3, TMS,
250 MHz) d 7.30±7.20 (m, 5H), 4.32 (t, 1H, Jˆ6.9 Hz),
3.82 (s, 2H), 2.56 (d, 2H, Jˆ6.9 Hz), 1.90 (bs, 2H), 1.19
(s, 3H), 1.17 (s, 3H); 13C NMR (CDCl3, 62.8 MHz) d 163.7
(s), 144.5 (s), 128.3 (d), 127.1 (d), 126.1 (d), 78.6 (d), 66.8
(s), 53.0 (t), 37.9 (t), 28.2 (q); HRMS (EI): calcd for
C13H18N2O 218.1419, found 218.1415. Anal. calcd for
C13H18N2O: C 71.53, H 8.31, N 12.83; found: C 71.39, H
8.43, N 12.64.
3.2.20. (4S,5S)-2-(2-Amino-2-p-tolyl)ethyl-4-methoxy-
methyl-5-phenyl-2-oxazoline (5n). Mixture of diastereo-
isomers; pale yellow oil; 1H NMR (CDCl3, TMS,
300 MHz) d 7.30±7.00 (m, 18H) 4.29 (m, 2H), 3.32 (s,
3H), 3.31 (s, 3H), 3.25 (m, 4H), 2.85 (m, 2H), 2.44 (m,
2H), 2.31 (s, 6H), 2.10 (bs, 4H); 13C NMR (CDCl3,
75 MHz) d 170.5 (s), 141.62 (s), 141.55 (s), 137.8 (s),
137.7 (s), 136.4 (s), 136.3 (s), 129.0 (d), 128.9 (d), 127.95
(d), 125.95 (d), 125.8 (d), 125.5 (d), 73.0 (t), 72.1 (t), 58.4
(q), 52.3 (d), 49.6 (d), 49.55 (d), 37.0 (t), 36.9 (t), 20.6 (q).
3.2.14. 2-(2-Amino-2-p-tolyl)ethyl-4,4-dimethyl-2-oxazo-
line (5j). Pale yellow oil; 1H NMR (CDCl3, TMS, 250 MHz)
d 7.23 (d, 2H, Jˆ8.0 Hz), 7.10 (d, 2H, Jˆ8.0 Hz), 4.32 (t,
1H, Jˆ6.9 Hz), 3.78 (s, 2H), 2.53 (d, 2H, Jˆ6.9 Hz), 2.19
(s, 3H), 2.10 (bs, 2H), 1.23 (s, 3H), 1.20 (s, 3H); 13C NMR
(CDCl3, 62.8 MHz) d 164.5 (s), 142.3 (s), 137.3 (s), 129.7
(d), 126.6 (d), 79.2 (d), 67.5 (s), 53.4 (t), 38.7 (t), 28.9 (q),
21.5 (q); HRMS (EI): calcd for C14H20N2O 232.1575, found
232.1571. Anal. calcd for C14H20N2O: C 72.38, H 8.68, N
12.06; found: C 72.27, H 8.53, N 11.91.
3.2.21. 2-(2-Cyclohexylamino-2-phenyl)ethyl-2-oxazoline
(5o). Pale yellow solid. Mp 98±1008C; H NMR (CDCl3,
1
TMS, 300 MHz) d 7.34±7.25 (m, 5H), 4.18 (m, 1H), 4.15 (t,
2H, Jˆ9.1 Hz), 3.78 (t, 2H, Jˆ9.4 Hz), 2.60±2.54 (m, 2H),
2.35±1.08 (m, 12H); 13C NMR (CDCl3, 100 MHz) d 167.2
(s), 144.5 (s), 129.2 (d), 128.0 (d), 127.8 (d), 68.0 (t), 57.5
(d), 55.1 (t), 54.1 (d), 38.1 (t), 35.4 (t), 33.5 (t), 26.9 (t), 26.0
(t), 25.6 (t); MS (EI) (m/z, %): 271 (M121, 14), 207
(M1265, 100), 188 (M1284, 57). Anal. calcd for
C17H24N2O: C 75.00, H 8.82, N 10.29; found: C 75.31, H
8.79, N 10.41.
3.2.15. 2-(2-Amino-2-p-methoxyphenyl)ethyl-4,4-dimethyl-
2-oxazoline (5k). Pale yellow oil; H NMR (CDCl3, TMS,
1
250 MHz) d 7.22 (d, 2H, Jˆ8.7 Hz), 6.79 (d, 2H,
Jˆ8.7 Hz), 4.27 (m, 1H), 3.81 (s, 2H), 3.72 (s, 3H), 2.47
(m, 2), 2.00 (bs, 2H), 1.19 (s, 3H), 1.16 (s, 3H); 13C NMR
(CDCl3, 62.8 MHz) d 165.6 (s), 145.4 (s), 143.9 (s), 129.3
(d), 126.7 (d), 80.4 (d), 68.5 (s), 52.9 (q), 42.6 (t), 35.5 (t),
21.5 (q); HRMS (EI): calcd for C14H20N2O2 248.1527,
found 248.1524. Anal. calcd for C14H20N2O2: C 67.72, H
8.12, N 11.28; found: C 67.75, H 8.13, N 11.30.
3.2.22. 2-(2-p-Methoxyphenylamino-2-phenyl)ethyl-2-
oxazoline (5p). Pale brown solid. Mp 107±98C; H NMR
1
(CDCl3, TMS, 300 MHz) d 7.43±7.21 (m, 5H), 7.70 (d, 2H,
Jˆ7.9 Hz), 7.50 (d, 2H, Jˆ7.9 Hz), 4.63 (dd, 1H, Jˆ13.5,

S. Fustero et al. / Tetrahedron 57 (2001) 703±712
709
8.2 Hz), 4.50 (bs, 1H), 4.20 (t, 2H, Jˆ9.3 Hz), 3.81 (t, 2H,
Jˆ9.3 Hz), 3.68 (s, 3H), 2.79±1.70 (m, 2H); 13C NMR
(CDCl3, 62.8 MHz) d 165.6 (s), 152.1 (s), 143.0 (s), 141.4
(s), 128.7 (d), 127.3 (d), 126.2 (d), 115.0 (d), 114.7 (d), 67.4
(t), 56.3 (t), 55.7 (q), 54.5 (d), 36.9 (t); MS (EI) (m/z, %):
296 (M1, 8), 208 (M1288, 89), 196 (M12100, 100). Anal.
calcd for C18H20N2O2: C 72.97, H 6.75, N 9.46; found: C
72.80, H 6.61, N 9.31.
1H NMR (CDCl3, TMS, 250 MHz) d 7.17±6.43 (m, 9H),
4.29 (d, 1H, Jˆ7.8 Hz), 4.09 (t, 2H, Jˆ9.3 Hz), 3.73 (t, 2H,
Jˆ9.3 Hz), 3.70 (s, 3H), 2.78 (m, 1H), 1.06 (d, 3H,
Jˆ7.3 Hz); 13C NMR (CDCl3, 62.8 MHz) d 169.5 (s),
158.6 (s), 147.2 (s), 133.6 (s), 128.9 (d), 127.9 (d), 116.9
(d), 113.5 (d), 113.2 (d), 67.1 (t), 60.0 (d), 55.1 (q), 54.1 (t),
40.8 (d), 15.7 (q). Anal. calcd for C19H22N2O2: C 73.55, H
7.09, N 9.03; found: C 73.71, H 7.01, N 9.18.
3.2.23. 2-[2-Phenyl-2-(N-1-phenylethylamino)]ethyl-2-
oxazoline (5q). Obtained as a non-separable mixture of
diastereoisomers in a 1:1 ratio. Pale yellow oil; H NMR
3.2.28. Method B: Reduction of D2-oxazoline protected
b-imino acids 4f,v,w. MeOH (3 mL) and NaBH4
(30.0 mmol) were added sequentially to a solution of the
corresponding iminic derivative 4f,v,w (20.0 mmol) in dry
THF (10 mL) at 08C. The reaction mixture was stirred and
allowed to reach room temperature. After 30 min the reac-
tion was ®nished (TLC monitoring) and saturated aqueous
solution of NH4Cl (4-5 mL) was added. The reaction
mixture was extracted with dichloromethane (3£15 mL);
the combined organic layer was washed with saturated
brine, dried over MgSO4, ®ltered, and solvents were evapo-
rated under reduced pressure to give a residue that was then
puri®ed by means of ¯ash chromatography over SiO2 to give
the corresponding D2-oxazoline protected b-amino acid
5f,v,w in the yield reported in Table 1.
1
(CDCl3, TMS, 250 MHz) d 7.28±6.96 (m, 20H), 4.10±3.93
(m, 4H), 3.78±3.52 (m, 6H), 3.35 (q, 2H, Jˆ7.0 Hz), 2.70±
2.30 (m, 4H), 1.20 (d, 3H, Jˆ7.0 Hz), 1.12 (d, 3H,
Jˆ7.0 Hz); 13C NMR (CDCl3, 50 MHz) d 166.1 (s), 145.9
(s), 145.4 (s), 143.1 (s), 128.4 (d), 128.3 (d), 128.2 (d), 127.1
(d), 127.0 (d), 126.9 (d), 126.6 (d), 126.5 (d), 67.0 (t), 57.3
(t), 56.9 (t), 54.8 (d), 54.5 (d), 54.3 (d), 36.9 (t), 36.3 (t), 25.0
(q), 22.3 (q). HRMS (FAB): calcd for C19H22N2O (M111)
295.1809, found 295.1810.
3.2.24. 2-(2-Anilino-2-p-methoxyphenyl)ethyl-2-oxazo-
line (5r). White solid. Mp 138±1408C; H NMR (CDCl3,
1
TMS, 250 MHz) d 7.35±6.46 (m, 9H), 4.70±4.57 (m1bs,
2H), 4.13 (t, 2H, Jˆ9.5 Hz), 3.73 (t, 2H, Jˆ9.5 Hz), 3.70 (s,
3H), 2.75±2.65 (m, 2H); 13C NMR (CDCl3, 62.8 MHz) d
165.5 (s), 158.7 (s), 147.1 (s), 134.6 (s), 129.0 (d), 127.2 (d),
117.4 (d), 114.1 (d), 113.6 (d), 67.3 (t), 55.2 (d), 54.8 (q),
54.4 (t), 36.9 (t); MS (EI) (m/z, %): 296 (M1, 7), 212
(M1284, 78), 211 (M1285, 83), 210 (M1286, 100).
Anal. calcd for C18H20N2O2: C 72.97, H 6.75, N 9.46;
found: C 72.89, H 6.70, N 9.58.
3.2.29. 2-(2-p-Methoxyphenylamino-3,3-dimethyl)butyl-
2-oxazoline (5f). White solid. Mp 115±6; 1H NMR
(CDCl3, TMS, 250 MHz) d 6.78±5.59 (m, 4H), 3.89 (m,
1H), 3.72 (s, 3H), 3.67±3.40 (m, 4H), 3.20 (bs, 1H), 2.55
(dd, 1H, Jˆ13.8, 3.8 Hz), 2.33 (dd, 1H, Jˆ13.8, 10.2 Hz),
0.98 (s, 9H); 13C NMR (CDCl3, 62.8 MHz) d 166.9 (s),
151.4 (s), 143.3 (s), 114.5 (d), 114.3 (d), 67.0 (t), 61.5 (d),
55.6 (q), 54.0 (t), 35.3 (s), 30.4 (t), 26.4 (q); MS (EI) (m/z,
%): 276 (M1, 18), 219 (M12t-Bu, 100); HRMS (EI): calcd
for C16H24N2O2 276.1838, found 276.1836.
3.2.25. (1Sp,2Rp)-2-(2-Anilino-1-methyl-2-phenyl)ethyl-
2-oxazoline (anti-5s). White solid. Mp 163±58C; 1H
NMR (CDCl3, TMS, 250 MHz) d 7.22±6.43 (m, 10H),
4.87 (d, 1H, Jˆ6.1 Hz), 4.33 (dd, 1H, Jˆ6.1 and 6.1 Hz),
4.06 (t, 2H, Jˆ9.0 Hz), 3.75 (t, 2H, Jˆ9.0 Hz), 2.78 (m,
1H), 1.06 (d, 3H, Jˆ7.3 Hz); 13C NMR (CDCl3,
62.8 MHz) d 169.4 (s), 147.1 (s), 141.7 (s), 128.9 (d),
128.4 (d), 127.3 (d), 126.9 (d), 117.0 (d), 113.2 (d), 67.2
(t), 60.6 (d), 54.1 (t), 40.7 (d), 15.8 (q); HRMS (EI): calcd
for C18H20N2O 280.1576, found 280.1577.
3.2.30. 2-[3,3-Dimethyl-2-(p-tolylamino)]butyl-2-oxazo-
line (5v). White solid. Mp 103±58C; H NMR (CDCl3,
1
TMS, 250 MHz) d 6.88 (d, 2H, Jˆ7.5 Hz), 6.48 (d, 2H,
Jˆ7.5 Hz), 4.00±3.90 (m, 1H), 3.67±3.40 (m, 4H), 3.30
(bs, 1H), 2.55 (dd, 1H, Jˆ13.0, 3.8 Hz), 2.31 (dd, 1H,
Jˆ13.0, 8.1 Hz), 2.18 (s, 3H), 0.90 (s, 9H); 13C NMR
(CDCl3, 62.8 MHz) d 167.1 (s), 146.7 (s), 129.4 (d),
125.9 (s), 113.4 (d), 67.1 (t), 60.6 (d), 54.1 (t), 35.5 (s),
30.4 (t), 26.5 (q), 20.3 (q); MS (EI) (m/z, %): 260 (M1,
12), 203 (M12t-Bu, 100); HRMS (EI): calcd for
C16H24N2O 260.1889, found 260.1882.
3.2.26. 2-[1-Methyl-2-phenyl-2-(N-1-phenylethylamino)]-
ethyl-2-oxazoline (5t). Obtained as a non-separable mixture
of four diastereoisomers in a 1:3:1:3 ratio; yellow oil; H
1
NMR (CDCl3, TMS, 250 MHz) d 7.30±7.00 (m, 20H), 4.20
(t, 4H, Jˆ7.6 Hz), 4.05±3.35 (m, 8H), 2. 64 (m, 1H), 2.55
(m, 1H), 1.92±1.79 (bs, 2H), 1.18 (d, 3H, Jˆ7.0 Hz), 1.08
(d, 3H, Jˆ7.0 Hz), 0.86 (d, 3H, Jˆ7.0 Hz), 0.75 (d, 3H,
Jˆ7.0 Hz); 13C NMR (CDCl3, 62.8 MHz) d 170.6 (s),
169.8 (s), 146.4 (s), 145.6 (s), 142.0 (s), 141.8 (s), 128.2
(d), 128.1(d), 127.7(d), 127.5 (d), 127.4 (d), 127.2 (d), 126.9
(d), 126.7 (d), 126.5 (d), 67.1 (t), 67.0 (t), 66.8 (t), 63.2 (d),
61.5 (d), 54.9 (d), 54.7 (d), 54.5 (d), 54.2 (t), 54.1 (t), 40.8
(d), 40.6 (d), 25.3 (q), 25.0 (q), 22.1 (q), 21.9 (q), 15.3 (q),
13.3 (q), 12.9 (q); HRMS (EI): calcd for C20H25N2O
(M111) 309.1967, found 309.1955.
3.2.31. (anti)-2-[1,3,3-Trimethyl-2-(p-tolylamino)]butyl-
2-oxazoline (anti-5w). White solid. Mp 117±88C; 1H
NMR (CDCl3, TMS, 250 MHz) d 6.86 (d, 2H, Jˆ7.5 Hz),
6.45 (d, 2H, Jˆ7.5 Hz), 4.75 (bs, 1H), 4.09±3.85 (m, 2H),
3.72±3.45 (m, 3H), 2.75 (m, 1H), 2.13 (s, 3H), 1.18 (d, 3H,
Jˆ7.1 Hz), 0.92 (s, 9H); 13C NMR (CDCl3, 62.8 MHz) d
171.4 (s), 147.1 (s), 129.5 (d), 125.6 (s), 112.9 (d), 67.0 (t),
62.4 (d), 54.1 (t), 37.2 (s), 35.3 (d), 27.4 (q), 20.3 (q), 17.0
(q); MS (EI) (m/z, %): 274 (M1, 20), 217 (M12t-Bu, 100);
HRMS (EI): calcd for C17H26N2O 274.2045, found
274.2042.
3.2.32. (syn)-2-[1,3,3-Trimethyl-2-(p-tolylamino)]butyl-
2-oxazoline (syn-5w). White solid. Mp 130±28C; 1H
NMR (CDCl3, TMS, 250 MHz) d 6.87 (d, 2H, Jˆ7.5 Hz),
3.2.27. (1Sp,2Rp)-2-(2-Anilino-2-p-methoxyphenyl-1-methyl)-
ethyl-2-oxazoline (anti-5u). White solid. Mp 168±1708C;

710
S. Fustero et al. / Tetrahedron 57 (2001) 703±712
6.50 (d, 2H, Jˆ7.5 Hz), 4.99 (bd, 1H, Jˆ9.8 Hz), 4.20±4.03
(m, 2H), 3.85±3.67 (m, 2H), 3.08 (dd, 1H, Jˆ9.8, 2.8 Hz),
2.96 (dd, 1H, Jˆ7.1, 2.8 Hz), 2.12 (s, 3H), 1.06 (d, 3H,
Jˆ7.1 Hz), 0.92 (s, 9H); 13C NMR (CDCl3, 62.8 MHz) d
170.6 (s), 148.3 (s), 129.7 (d), 124.8 (s), 112.3 (d), 66.6 (t),
65.3 (d), 54.1 (t), 36.8 (s), 34.3 (d), 27.2 (q), 20.3 (q), 18.9 (q);
MS (EI) (m/z, %): 274 (M1, 12), 217 (M12t-Bu, 100);
HRMS (EI): calcd for C17H26N2O 274.2045, found 274.2045.
322.1681, found 322.1681. Anal. calcd for C20H22N2O2: C
74.51, H 6.88, N 8.69; found: C 74.37, H 6.95, N 8.63.
3.3.4. One-pot synthesis of N-substituted C-protected b-
amino acids 5 from D2-oxazolines 1. n-BuLi (14.0 mmol,
2.5 M in hexanes) was added dropwise to a solution of
diisopropylamine (14.0 mmol) in dry THF (10 mL) at
2208C under inert atmosphere. After 30 min the reaction
was cooled down to 2788C and a THF (10 mL) solution of
the corresponding 2-alkyl-D2-oxazoline (14.0 mmol) was
slowly added. The reaction was stirred at 2788C for 1 h,
before the dropwise addition of a solution of the correspond-
ing nitrile 2 (14.23 mmol) in dry THF (10 mL). After two
hours of stirring at low temperature, a solution of the alkyl
halide (14.23 mmol) in dry THF (10 mL) was added and the
reaction was stirred at room temperature for 3 h. When the
alkylation was not required, this step was omitted. The
progress of the reaction was followed by means of TLC
and when the a-alkylated intermediate 4 was observed to
be the main product, excess of Na and i-PrOH (4 mL) were
added. The reaction was again monitored by means of TLC
and was completed after 3±4 h. Work-up of the reaction as
described above gave N-substituted C-protected b-amino
acids 5 in one-pot from D2-oxazolines 1 in the yields
reported in Table 1.
3.3. Synthesis of N-benzoyl derivatives 5x±z
A solution of 4-N,N-Dimethylaminopyridine (DMAP)
(catalytic amount) and Et3N (12.0 mmol) in dichloro-
methane (10 mL) was added dropwise to a solution of the
corresponding N-unsubstituted compound 5 (11.0 mmol) in
dichloromethane (10 mL) at 08C under inert atmosphere. A
solution of benzoyl chloride (11 mmol) in dichloromethane
(10 mL) was then added dropwise at 08C. The reaction was
allowed to reach room temperature and stirred for 5±7 h
until TLC monitoring indicated complete disappearance of
the starting material. Solvents were evaporated under
reduced pressure to give a solid residue that was treated
with 1N HCl (25 mL) and extracted with ethyl acetate
(3£20 mL). The combined organic layer was washed
several times with saturated brine, dried over MgSO4, and
®ltered. After evaporation of the solvents, a solid residue
was obtained and then recrystallised with hexane±dichloro-
methane (3:1) to get N-benzoyl derivatives 5x±z in the
yields reported in Table 1.
3.3.5. Reduction of D2-thiazoline protected b-enamino
acid 7a. Isopropanol (3 mL, via syringe) and Na (excess)
in small portions were added sequentially under inert
atmosphere to a solution of the starting material 7a (4.1 g,
20.0 mmol) in dry THF (10 mL) at 08C. The reaction
mixture was stirred and allowed to reach room temperature.
When TLC monitoring indicated complete disappearance of
the starting material (2±6 h), the reaction was worked-up as
described above for the reduction of D2-oxazoline protected
b-enaminoacids 4. The oily residue obtained was identi®ed
as diamine thiol 8a (58%) and was not fully characterised.
3.3.1. 2-(2-Phenyl-2-phenylcarboxamido)ethyl-2-oxazo-
line (5x). White solid. Mp 134±78C; H NMR (CDCl3,
1
TMS, 250 MHz) d 8.18 (d, 1H, NH, Jˆ7.7 Hz), 7.88±
7.24 (m, 10H), 5.63 (m, 1H), 4.18 (t, 2H, Jˆ8.9 Hz), 3.82
(t, 2H, Jˆ8.9 Hz), 2.91 (m, 2H); 13C NMR (CDCl3,
62.8 MHz) d 166.4 (s), 165.8 (s), 141.0 (s), 134.5 (s),
131.5 (d), 128.5 (d), 127.4 (d), 127.1 (d), 126.2 (d), 67.1
(d), 54.3 (t), 49.9 (t), 33.7 (t); HRMS (EI): calcd for
C18H18N2O2 294.1378, found 294.1368. Anal. calcd for
C18H18N2O2: C 73.45, H 6.16, N 9.52; found: C 73.52, H
6.21, N 9.38.
3.3.6. 6-Amino-4-aza-6-phenyl-hexanethiol (8a). Yellow
oil; H NMR (CDCl3, TMS, 200 MHz) d 7.25±7.10 (m,
1
5H), 3.90 (t, 2H), 2.65 (m, 1H), 2.53 (t, 2H), 1.76 (m, 2H),
1.63 (s, 1H); 13C NMR (CDCl3, 50 MHz) d 146.2 (s), 128.3
(d), 126.8 (d), 126.0 (d), 54.7 (d), 47.6 (t), 46.8 (t), 39.1 (t),
38.5 (t).
3.3.2. 2-[(1Rp,2Sp)-1-Methyl-2-phenyl-2-phenylcarboxa-
mido)ethyl-2-oxazoline (anti-5y). White solid. Mp 126±
98C; H NMR (CDCl3, TMS, 250 MHz) d 8.60 (d, 1H,
1
NH, Jˆ8.7 Hz), 7.84±7.18 (m, 10H), 5.28 (dd, 1H, Jˆ8.7
and 4.6 Hz), 4.10 (m, 2H), 3.75 (m, 2H), 3.01 (m), 1.28 (d,
3H, Jˆ7.2 Hz); 13C NMR (CDCl3, 75 MHz) d 170.8 (s),
167.5 (s), 142.0 (s), 135.3 (s), 129.4 (d), 129.2 (d), 129.1
(d), 128.1 (d), 128.0 (d), 127.2 (d), 67.7 (t), 56.4 (t), 55.0 (d),
39.6 (d), 18.0 (q); HRMS (EI): calcd for C19H20N2O2
308.1525, found 308.1524. Anal. calcd for C19H20N2O2: C
74.00, H 6.54, N 9.08; found: C 74.23, H 6.43, N 9.18.
3.4. Synthesis of N-unsubstituted b-amino acids 9a±d
A
solution of the corresponding compound 5a±d
(2.5 mmol) in 3N HCl (50 mL) was re¯uxed for 2±3 h.
The reaction was allowed to cool to room temperature and
was extracted with diethyl ether (3£25 mL). The aqueous
layer was evaporated under reduced pressure (1022 mmHg)
to give a white solid residue. The free b-amino acid 9 was
isolated by passing the residue through a Dowex 50wx8 ion-
exchange chromatography column. For this procedure, the
ion exchange column was ®rst rinsed with distilled water; an
aqueous solution of the residue was then deposited on the
top of the column and eluted with 1.5 M NH4OH. Evapora-
tion of the fractions under reduced pressure (1022 mmHg)
gave the corresponding free amino acid 9 as a white solid.
Yields are listed in Table 2.
3.3.3. 4,4-Dimethyl-2-(2-phenyl-2-phenylcarboxamido)-
ethyl-2-oxazoline (5z). White solid. Mp 107±1108C; H
1
NMR (CDCl3, TMS, 300 MHz) d 8.01 (d, 1H, NH,
Jˆ8.0 Hz), 7.82±7.15 (m, 10H), 5.53 (m, 1H), 3.78 (s,
2H), 2.79 (d, 2H, Jˆ5.7 Hz), 1.16 (s, 3H), 1.12 (s, 3H);
13C NMR (CDCl3, 62.8 MHz) d 167.0 (s), 163.8 (s),
156.2.0 (s), 141.6 (s), 135.0 (d), 132.2 (d), 129.2 (d),
128.1 (d), 127.8 (d), 127.0 (d), 79.6 (d), 67.9 (t), 50.7 (t),
34.8 (s), 29.0 (q); HRMS (EI): calcd for C20H22N2O2
3.4.1. 3-Amino-3-phenylpropionic acid 9a. Mp 221±38C

S. Fustero et al. / Tetrahedron 57 (2001) 703±712
711
(dec.); 1H NMR (D2O, 250 MHz) d 7.20±7.05 (m, 5H), 4.02
Acknowledgements
We are grateful to the DGES (PB97-0760-C02-01) and to
(t, 1H, Jˆ7.5 Hz), 2.35 (d, 2H, Jˆ7.6 Hz); 13C NMR (D2O,
62.8 MHz) d 180.9 (s), 145.3 (s), 129.5 (d), 128.1 (d), 127.1
(d), 53.7 (d), 47.7 (t); HRMS (EI): calcd for C9H11NO2
165.0789, found 165.0802.
Â
the Ministerio de Educacion y Cultura, Generalitat
Valenciana, and Universidad de Valencia for predoctoral
fellowships to M. D. D., E. S., and A. N., respectively.
3.4.2. 3-Amino-3-(4-methylphenyl)propionic acid 9b. Mp
240±28C (dec.); 1H NMR (D2O, 250 MHz) d 7.09±6.99 (m,
4H), 3.99 (t, 1H, Jˆ7.6 Hz), 2.37 (d, 2H, Jˆ7.6 Hz), 2.09 (s,
3H); 13C NMR (D2O, 62.8 MHz) d 181.0 (s), 142.3 (s),
138.1 (s), 130.0 (d), 127.1 (d), 53.3 (d), 47.1 (t), 20.8 (q);
HRMS (EI): calcd for C10H13NO2 179.0946, found
179.0956. Anal. calcd for C10H13NO2: C 67.02, H 7.31, N
7.82; found: C 67.15, H 7.23, N 7.87.
References
1. Koert, U. Angew. Chem., Int. Ed. Engl. 1997, 36, 1836±1837.
2. For reviews see: (a) Seebach, D.; Matthews, J. L. Chem.
Commun. 1997, 2015±2022. (b) Gellman, S. H. Acc. Chem.
Res. 1998, 31, 173±180. For more recent references see:
(c) Wu, Y.-D.; Wang, D.-P. J. Am. Chem. Soc. 1998, 120,
13485±13493. (d) Applequist, J.; Bode, K. A.; Appella,
D. H.; Christianson, L. A.; Gellman, S. H. J. Am. Chem.
Soc. 1998, 120, 4891±4892. (e) Seebach, D.; Matthews,
J. L.; Meden, A.; Wassels, T.; Baerlocher, C.; McCusker,
L. B. Helv. Chim. Acta 1997, 80, 173±182. (f) Hartgerink,
J. D.; Clark, T. D.; Ghadiri, M. R. Chem. Eur. J. 1998, 4,
1367±1372. (g) Clark, T. D.; Buehler, L. K.; Ghadiri, M. R.
J. Am. Chem. Soc. 1998, 120, 651±656.
3.4.3. 3-Amino-3-(4-methoxyphenyl)propionic acid 9c.
Mp 238±2408C (dec.); H NMR (D2O, 250 MHz) d 7.17
1
(d, 2H, Jˆ8.7 Hz), 6.81 (d, 2H, Jˆ8.7 Hz), 4.36 (t, 1H,
Jˆ7.6 Hz), 3.61 (s, 3H), 2.56±2.64 (dq, 2H, Jˆ11.0,
7.0 Hz); 13C NMR (D2O, 62.8 MHz) d 177.3 (s), 159.5
(s), 128.6 (d), 114.6 (d), 55.4 (q), 52.3 (d), 40.5 (t)Ða
C(s) around 138 ppm was not observed; HRMS (EI):
calcd for C10H13NO3 195.0895, found 195.0897. Anal.
calcd for C10H13NO3: C 61.54, H 6.67, N 7.18; found: C
61.59, H 6.73, N 7.15.
3. Hinterman, T.; Seebach, D. Chimia 1997, 51, 244±247.
4. For reviews regarding the natural occurrence of b-amino acids
see: (a) Cardillo, G.; Tomasini, C. Chem. Soc. Rev. 1996,
117±128. (b) Bewley, C. A.; Faulkner, D. J. Angew. Chem.,
Int. Ed. Engl. 1998, 37, 2162±2178. See also: (c) Schumacher,
K. K.; Hauze, D. B.; Jiang, J.; Szewczyck, J.; Reddy, R. E.;
3.4.4. (2Rp,3Sp)-3-Amino-2-methyl-3-phenylpropionic acid
anti-9d. Mp 256±88C (dec.); H NMR (D2O, 250 MHz) d
7.20±7.05 (m, 5H), 3.59 (d, 1H, Jˆ8.0 Hz), 2.32±2.25 (m,
1H), 0.57 (d, 3H, Jˆ7.0 Hz); 13C NMR (D2O, 62.8 MHz) d
185.2 (s), 143.8 (s), 129.4 (d), 128.2 (d), 59.6 (d), 51.6 (d),
16.1 (q); HRMS (EI): calcd for C10H14NO2 (M111)
180.1024, found 180.1022.
1
Â
Davis, F. A.; Joullie, M. M. Tetrahedron Lett. 1999, 40, 455±
458 and references cited therein. (d) Fujii, K.; Sivonen, K.;
Kashiwagi, T.; Hirayama, K.; Harada, K.-I. J. Org. Chem.
1999, 64, 5777±5782. (e) Nicolaou, K. C.; Guy, R. K.
Angew. Chem., Int. Ed. Engl. 1995, 34, 2079±2090. (f)
Mukaiyama, T.; Shiina, I.; Iwadare, H.; Saitoh, M.;
Nishimura, T.; Ohkawa, N.; Sakoh, H.; Nishimura, K.;
Tani, Y.-I.; Hasegawa, M.; Yamada, K.; Saitoh, K. Chem.
Eur. J. 1999, 5, 121±161.
3.4.5. Synthesis of N-substituted b-amino acids 9e±f. A
solution of the corresponding compound 9e±f (5.0 mmol) in
3N HCl (50 mL) was re¯uxed for 2.5 h. The reaction was
allowed to cool to room temperature, neutralised with 3N
NaOH, and extracted with chloroform (3£10 mL). The
combined organic phase was dried with MgSO4, ®ltered,
and evaporated under reduced pressure. The free b-amino
acid was puri®ed from the residue by means of ¯ash chro-
matography over silica gel, with concomitant recovery of
the aminoalcohol moiety. Finally, recrystallisation in hex-
ane±chloroform 3:1 afforded the corresponding b-amino
acid.
5. Spatola, A. F. In Chemistry and Biochemistry of the Amino
Acids, Peptides and Proteins, Weinstein, B., Ed., Marcel
Dekker: New York, 1983; 7, pp 331.
6. (a) Colombo, L.; Rassu, G.; Spanu, P. J. Org. Chem. 1991, 56,
6523±6527. (b) Robl, J. A.; Cimarusti, M. P.; Simpkins, L.
M.; Weller, H. N.; Pan, Y. Y.; Malley, M.; DiMarco, J. D.
J. Am. Chem. Soc. 1994, 116, 2348±2355. (c) Kawabata, K.;
Inamoto, Y.; Sakane, K.; Iwamoto, T.; Hashimoto, S.
J. Antibiot. 1990, 43, 513±518.
3.4.6. 3-Phenyl-3-N-phenylaminopropionic acid 9e.
White solid. Mp 135±68C; 1H NMR (CDCl3, TMS,
200 MHz) d 7.38±6.58 (m, 10H), 6.10±5.00 (bs, 2H),
4.85 (t, 1H, Jˆ6.2 Hz), 2.85 (d, 2H, Jˆ6.2 Hz); 13C NMR
(CDCl3, 62.8 MHz) d 176.5 (s), 146.4 (s), 141.7 (s), 129.1
(d), 128.8 (d), 127.5 (d), 126.2 (d), 118.2 (d), 114.0 (d), 54.8
(d), 42.4 (t); HRMS (EI): calcd for C15H15NO2 241.1103,
found 241.1115.
7. (a) Hart, D.; Chan, D. Chem. Rev. 1989, 89, 1447±1465.
(b) Palomo, C.; Aizpurua, J. M.; Urchequi, R.; Iturburu, M.;
Ochoa, A.; Cuevas, C. J. Org. Chem. 1991, 56, 2244±2247
(references cited therein).
8. For recent reviews on b-amino acids, see: (a) Juaristi, E.;
Quintana, D.; Escalante, J. Aldrichimica Acta 1994, 27, 3±
11. (b) Cole, D. C. Tetrahedron 1994, 50, 9517±9582.
(c) In Enantioselective Synthesis of b-Amino Acids; Juaristi,
3.4.7. 3-N-p-Methoxyphenylamino-4,4-dimethylpentanoic
acid 9f. White solid. Mp 125±78C; H NMR (CD3OD,
1
Â
E., Ed.; VCH: New York, 1996. (d) Juaristi, E.; Lopez-Ruiz, H.
Curr. Med. Chem. 1999, 6, 983±1004.
TMS, 250 MHz) d 6.70 (d, 2H, Jˆ9.0 Hz), 6.59 (d, 2H,
Jˆ9.0 Hz), 3.66 (s, 3H), 3.50 (dd, 1H, Jˆ8.7, 4.7 Hz),
2.56 (dd, 1H, Jˆ15.0, 4.7 Hz), 2.27 (dd, 1H, Jˆ15.0,
8.7 Hz), 0.87 (s, 9H); HRMS (EI): calcd for C14H21NO3
251.1521, found 251.1517.
9. (a) Davies, S. G.; Garrido, N. M.; Ichichara, O.; Walters, I. A.
S. J. Chem. Soc., Chem. Commun. 1993, 1153±1155.
(b) Sibi, M. P.; Shay, J. J.; Liu, M.; Jasperse, C. P. J. Am.
Chem. Soc. 1998, 120, 6615±6616.

712
S. Fustero et al. / Tetrahedron 57 (2001) 703±712
10. (a) Kunz, H.; Burgard, A.; Schanzenbach, D. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 386±387. (b) Moody, C. J.; Hunt, J. C.
A. Synlett 1998, 733±734.
chemistry have been described: (a) Shono, T.; Kise, N.; Sanda,
F.; Ohi, S.; Tsubata, K. Tetrahedron Lett. 1988, 29, 231±234.
(b) Shimano, M.; Meyers, A. I. J. Org. Chem. 1995, 60, 7445±
7455.
11. (a) Juaristi, E.; Quintana, D.; Lamatsch, B.; Seebach, D.
J. Org. Chem. 1991, 56, 2553±2257. (b) Braschi, I.;
Cardillo, G.; Tomasini, C.; Venezia, R. J. Org. Chem. 1994,
59, 7292±7298.
Â
20. (a) Fustero, S.; Dõaz, D.; Barluenga, J.; Aguilar, E. Tetrahe-
Â
dron Lett. 1992, 33, 3801±3804. (b) Fustero, S.; Dõaz, M. D.;
Asensio, A.; Navarro, A.; Kong, J.-S.; Aguilar, E. Tetrahedron
1999, 55, 2695±2712.
Â
21. Fustero, S.; Navarro, A.; Dõaz, D.; G. de la Torre, M.;
12. (a) MuÈller, A.; Vogt, C.; Sewald, N. Synthesis 1998, 837±841.
(b) Sokolov, V. V.; Kozhushkov, S. I.; Nikolskaya, S.;
Belov, V.; Es-Sayed, M.; de Meijere, A. Eur. J. Org. Chem.
1998, 777±783.
Â
Asensio, A.; Sanz, F.; Liu Gonzalez, M. J. Org. Chem.
1996, 61, 8849±8859.
22. Bertilsson, S. K.; Tedenborg, L.; Alonso, D. A.; Andersson,
P. G. Organometallics 1999, 18, 1281±1286.
Â
23. Preliminary communication: Fustero, S.; Dõaz, M. D.;
Navarro, A.; Salavert, E.; Aguilar, E. Tetrahedron Lett.
1999, 40, 1005±1008.
13. Gmeiner, P. Tetrahedron Lett. 1990, 31, 5717±5720.
14. Chu, K. S.; Negrete, G. R.; Konopelski, J. P.; Lakner, F. J.;
Woo, N.-T.; Olmstead, M. M. J. Am. Chem. Soc. 1992, 114,
1800±1812.
15. (a) Soloshonok, V. A. In Enantioselective Synthesis of b-
Amino Acids; Juaristi, E., Ed.; VCH: New York, 1996; pp
443±464 (references cited therein). (b) Brieva, R.; Crich, J.
Z.; Sih, J. Org. Chem. 1993, 58, 1068±1075. (c) Cardillo, G.;
Gentilucci, L.; Tolomelli, A.; Tomasini, C. J. Org. Chem.
1998, 63, 2351±2353.
24. Barluenga, J.; Olano, B.; Fustero, S. J. Org. Chem. 1983, 48,
2255±2259.
25. Barluenga, J.; Aguilar, E.; Fustero, S.; Viado, A. L.; Olano, B.
J. Org. Chem. 1992, 57, 1219±1223.
26. Tse, B.; Kishi, Y. J. Org. Chem. 1994, 59, 7807±7814.
27. Meyers, A. I.; McKennon, M. J.; Drauz, K.; Schwarn, M. J.
Org. Chem. 1993, 58, 3568±3571.
16. (a) Palmieri, M.; Bartoli, G.; Cimarelli, C.; Marcantoni, E.;
Petrini, G. J. Org. Chem. 1994, 59, 5328±5335. (b)
Palmieri, G.; Cimarelli, C. J. Org. Chem. 1996, 61, 5557±
5563.
28. Stuk, T.; Haight, A.; Scarpetti, D.; Allen, M.; Menzia, J.;
Robbins, T.; Parekh, S.; Tien, J.-H.; Pariza, R.; Kerdesky, F.
J. Org. Chem. 1994, 59, 4040±4041.
17. For other methods that do not ®t in the previously described
classi®cation, see: (a) Axten, J. M.; Ivy, R.; Krim, L.; Winkler,
J. D. J. Am. Chem. Soc. 1999, 121, 6511±6512. (b) Evans, D.
A.; Wu, L. D.; Wiener, J. J. M.; Johnson, J. S.; Ripin, D. H. B.;
Tedrow, J. S. J. Org. Chem. 1999, 64, 6411±6417.
18. For recent reviews of oxazolines, see: (a) Lutowski, K. A.;
Meyers, A. I. In Asymmetric Synthesis; Morrison, J. D., Ed.;
Academic: Orlando, 1984; Vol. 3, pp 213±274. (b)
Reuman, M.; Meyers, A. I. Tetrahedron 1985, 41, 837±860.
(c) Meyers, A. I.; Gant, T. G. Tetrahedron 1994, 50, 2297±
2360. See also: (d) Aguilar, E.; Meyers, A. I. Tetrahedron Lett.
1994, 35, 2477±2480. (e) Meyers, A. I.; Tavares, F. X. J. Org.
Chem. 1996, 61, 8207±8215.
29. Sun, Y.; Anderson, C. J.; Pajeau, T. S.; Reichert, D. E.;
Hancock, R. D.; Motekatis, R. J.; Martell, A. E.; Welch, M.
J. Med. Chem. 1996, 39, 458±470.
30. Nutaitis, C. F.; Schultz, R. A.; Obaza, J.; Smith, F. X. J. Org.
Chem. 1980, 45, 4606±4608.
31. Kawecki, R.; Kozerski, L.; Urbanczyk-Lipkowska, Z.;
Bocelli, G. J. Chem. Soc., Perkin Trans. 1 1991, 2255±2260.
32. Thompson, D. K.; Suzuki, N.; Hegedus, L. S.; Satoh, Y. J.
Org. Chem. 1992, 57, 1461±1467.
33. (a) Frenette, R.; Monette, M.; Bernstein, M. A.; Young, R. N.;
Verhoeven, T. R. J. Org. Chem. 1991, 56, 3083±3089. (b)
Giovannini, R.; Petrini, M. Tetrahedron Lett. 1997, 38,
2123±2126.
19. Two methods to prepare b-Amino acids involving oxazoline-