Asymmetric 1,4-addition of oxazolones to nitroalkenes by bifunctional cinchona alkaloid thiourea organocatalysts: synthesis of α,α- disubstituted α-amino acids

Article abstract of DOI:10.1002/chem.200802030

An easy and simple synthetic approach to optically active α,α-quaternary a-amino acids using asymmetric organocatalysis is presented. The addition of oxazolones to nitroalkenes catalyzed by thiourea cinchona derivatives provides the corresponding α,α-quaternary α-amino acid derivatives with good yields, excellent diastereoselectivities (up to 98% dr), and from moderate to good enantioselectivities (up to 92% ee). The reaction can be performed on a large scale. The optically active oxazolone-nitroalkene addition products can be opened in a one-pot reaction to the corresponding esteramide derivatives. Additional transformations are also presented, such as the synthesis of amino esters, amino acids, and transformation into 3,4-disubstituted pyrrolidin-2-ones.

Full text of DOI:10.1002/chem.200802030

DOI: 10.1002/chem.200802030
Asymmetric 1,4-Addition of Oxazolones to Nitroalkenes by Bifunctional
Cinchona Alkaloid Thiourea Organocatalysts: Synthesis of a,a-Disubstituted
a-Amino Acids
Josꢀ Alemꢁn, Andrea Milelli, Silvia Cabrera, Efraim Reyes, and
Karl Anker Jørgensen*[a]
Abstract: An easy and simple synthetic
approach to optically active a,a-quater-
nary a-amino acids using asymmetric
organocatalysis is presented. The addi-
tion of oxazolones to nitroalkenes cata-
lyzed by thiourea cinchona derivatives
provides the corresponding a,a-quater-
nary a-amino acid derivatives with
good yields, excellent diastereoselectiv-
ities (up to 98% dr), and from moder-
ate to good enantioselectivities (up to
92% ee). The reaction can be per-
formed on a large scale. The optically
active oxazolone–nitroalkene addition
products can be opened in a one-pot
reaction to the corresponding ester–
amide derivatives. Additional transfor-
mations are also presented, such as the
synthesis of amino esters, amino acids,
and transformation into 3,4-disubstitut-
ed pyrrolidin-2-ones.
Keywords: amino acids · organo-
catalysis · oxazolones · thiourea
Introduction
products of nitroalkanes are also attractive substrates which
can be used due to the numerous transformations that allow
further reactions towards the nitro functionality, and also
allow us to study the non-covalent method for the addition
of important oxazolones to nitroalkenes. To the best of our
knowledge, this reaction has been never explored before.
Peptides and proteins are an area of interest in bioorganic
chemistry.[6] The synthesis of non-natural amino acids is an
important target as these compounds can be incorporated
into the peptide chain and might cause a dramatically
change in the properties of, for example, proteins. The a,a-
disubstituted quaternary a-amino acids are a particular class
of non-natural amino acids of particular importance.[7] There
are several reasons for the importance of these a,a-disubsti-
tuted a-amino acids; they increase the stability of proteins
avoiding in vivo racemization, restrict the conformational
flexibility, which is highly important for, for example, the
secondary structure of proteins, and which can lead to an
improvement of the resistance against chemical and enzy-
matic degradation.[8] Furthermore, a,a-disubstituted quater-
nary a-amino acids are also present in some antibiotics (for,
e.g., lactacystin).[9]
In the last few years, organocatalysis has proved to be a
powerful tool in the development of a large number of
enantioselective reactions.[1] During the development of or-
ganocatalytic methodologies, the asymmetric 1,4-conjugate
additions have emerged as powerful strategies to obtain
chiral organic compounds in an easy way.[2] There are two
main organocatalytic activation modes for carrying out the
1,4 addition: i) a covalent strategy, which often takes place
after the formation of an iminium ion by the reaction of an
unsaturated carbonyl compound with a chiral amine,[3] or ii)
a non-covalent activation method in which, for example, the
cinchona alkaloids represent a cornerstone in the functional-
ization of nitroalkenes.[4] Using the former concept, we have
recently reported the addition of oxazolones to a,b-unsatu-
rated aldehydes using secondary amines as catalysts obtain-
ing excellent enantioselectivities and good diastereoselecti-
vies.[5] However, we believe that optically active addition
[a] Dr. J. Alemꢀn, A. Milelli, Dr. S. Cabrera, Dr. E. Reyes,
Prof. Dr. K. A. Jørgensen
The importance of a,a-disubstituted a-amino acids has
caused an increased interest in the development of efficient
methodologies for the asymmetric synthesis of these valua-
ble optically active compounds. One of the synthetic chal-
lenges is to develop procedures that provide flexible and
Danish National Research Foundation Center for Catalysis
Department of Chemistry, Aarhus University
8000 Aarhus C (Denmark)
Fax : (+45)8919-6199
E-mail: kaj@chem.au.dk
10958
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Chem. Eur. J. 2008, 14, 10958 – 10966

FULL PAPER
simple methods for obtaining optically active a,a-disubsti-
tuted a-amino acids and which, furthermore, give diversity
in structural and electronic properties.
method developed by Soꢂs et al.[18] This method applies
modified Mitsunobu conditions, obtaining the amine inter-
mediate with inversion of configuration from the corre-
sponding commercial available cinchona alcohols 3a–d.
Therefore, the catalysts 4a–d were obtained by addition of
the intermediate amine to 3,5-bis(trifluoromethyl)phenyl-
isothiocyanate (Scheme 2). It was our hope that these cata-
lysts might give good results for the addition of oxazolones
to nitroalkenes. Table 1 presents some of the screening re-
sults, in which racemic oxazolones rac-1a,b are reacted with
nitroalkene 2a using catalysts 4a–d (5 mol%).
Several different catalytic approaches have been devel-
oped for the synthesis of optically active amino acids.[10]
Thus, one classical procedure for the synthesis of a-amino
acid derivatives is the Strecker reaction.[11] This reaction is
well-established for the asymmetric synthesis of chiral a-
substituted amino acids starting from aldimines, although
the synthesis of chiral a,a-disubstituted a-amino acids using
ketimines is now in progress, but shows some limitations.[12]
These limitations are related to the lower reactivity and
easy enolization of the ketimines, as well as the difficulties
to synthesize them. A more recent approach for the prepa-
ration of optically active a,a-disubstituted a-amino acids is
the alkylation of imines derived from Schiff bases with
chiral phase-transfer catalysis.[13]
Oxazolones are masked amino acids, but the use of these
compounds for the synthesis of amino acid derivatives is
more scarce.[14] These aza species have been mainly em-
ployed as an electrophile source; for example, in the Steg-
lich reaction which generates a,a-disubstituted amino acids
by ring-opening reaction of chiral oxazolones.[15] The use of
oxazolones as nucleophiles has only been shown in a few ex-
amples using metal catalysis for these funtionalizations.[16]
In this work we present our efforts to use the racemic ox-
azolones 1 as masked amino acid nucleophiles and their re-
action with nitroalkenes 2 to afford the corresponding opti-
cally active addition products with two new chiral centers, in
which one is a quaternary and the other a tertiary center
(Scheme 1). The optically products obtained are highly fun-
tionalized molecules, containing nitro, ester and imine
groups, which allow us to create diversity-oriented synthesis
using different reactions.
Scheme 2. Synthesis of bifunctional thiourea catalyst 4a–d used in this
work.
The results in Table 1 show that full conversion was ob-
tained when catalyst 4a,c were used at RT with the oxazo-
lone 1a in toluene as the solvent, and the addition product
5a was formed in a 90:10 diastereomeric ratio, 44 and 20%
ee, respectively (Table 1, entries 1, 2). The enantioselectivity
of the major diastereomer was increased to 74% ee when
the temperature was decreased to À248C using 4c as the
catalyst (Table 1, entry 3). No improvement of the enantio-
selectivity was obtained when lower temperature, such as
À788C, was applied. Thus, at À408C the enantioselectivity
was 58 and 68% ee with catalyst 4a and c, respectively
(Table 1, entries 4, 5). Solvents as CH2Cl2 and xylene did not
improve the enantioselectivity (Table 1, entries 7–9). Further
attempts to increase the enantioselectivity by for example,
lowering the concentration (0.2 and 0.1m) did not give any
improvements (Table 1, entries 10, 11). However, a change
in the structure of the nucleophile by using 1b, a tert-butyl
instead of p-tolyl as the R group (Table 1, entries 12–16)
gave an increase of the enantioselectivity. The highest enan-
tioselectivity was obtained when catalyst 4c was used at
À248C in toluene where 83% ee was obtained (Table 1,
entry 14).
Scheme 1. Organocatalytic enantioselective synthesis of optically active
a,a-disubstituted-a-amino acids.
Results and Discussion
Our initial screening reactions between the oxazolone and
the a,b-unsaturated nitroalkene occur in the presence of cin-
chona alkaloid derivatives 3 as the catalyst. Unfortunately,
our preliminary results showed that only rather low enantio-
selectivity was obtained with this catalyst system. However,
it has been found that, bifunctional thiourea cinchona alka-
loid catalysts can be used with good results for reactions
with nitroalkenes as electrophile partner.[17] These thiourea
cinchona alkaloid catalysts 4a–d are really accessible from
commercial available cinchona alkaloids by using the
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K. A. Jørgensen et al.
methyl substituent,
Table 1. Screening of various reaction conditions.[a]
with
a
giving the oxazolone derivative
5h (Table 2, entry 7) and a thio-
ether alkyl chain (5i) (Table 2,
entry 8).
The results in Table 2, in
which the electrophile—the
nitroalkene—was varied, gave
us interesting compounds with
two stereocenters in good yield,
diastereomeric ratio, and from
moderate to good enantioselec-
tivity. It should be noted that
these compounds have different
masked functions that could be
transformed (see below).
We have also studied the ad-
dition of different oxazolones
1a–h to nitroalkenes 2 and the
results are shown in Table 3.
The reaction took place with ar-
omatic ring imine function at
R2, aromatic and alkyl groups
(R1) at C-4/2. Thus, compounds
5a and j were obtained with
high diastereomeric ratio and
Entry
Cat.
T
1
Solvent
dr[b]
ee [%][c]
1
2
3
4
5
6
7
8
4c
4a
4c
4c
4a
4b
4c
4c
4c
4c
4c
4a
4b
4c
4d
4c
RT
RT
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
Tol
Tol
Tol
Tol
Tol
Tol
90:10
90:10
91:9
94 :6
97:3
91:9
90:10
83:17
80:20
44
À20
74
À24
À40
À40
À24
RT
À24
À24
À24
À24
À30
À30
À24
À30
À30
68
À58
À48
50
52
57
CH2Cl2
CH2Cl2
Xyl
9
10
11
12
13
14
15
16
Tol[d]
Tol[e]
Tol
91:9
92:8
53
55
>95:<5
>95:<5
>95:<5
>95:<5
>95:<5
70[f]
53[f]
83[f]
À54[f]
80[f]
Tol
Tol
Tol
Tol
[a] Performed with 1 (0.20 mmol), 2 (0.21 mmol) and catalyst 4 (5 mol%) in the corresponding solvent
(0.2 mL). All the reactions were stopped after 16 h, and full conversion was observed in all the cases. [b] De-
termined by 1H NMR spectroscopy [c] Determined by chiral-stationary phase HPLC. [d] Performed at 0.2m.
[e] Performed at 0.1m. [f] ee was determined by transformation to product 6b (see below).
With these conditions at hand we investigated the scope
of different nitroalkenes 2 and oxazolone 1b as the nucleo-
phile (Table 2). For every entry in the table we have
checked the four catalysts 4a–d (Scheme 2) and the best re-
sults of every reaction are shown. The reaction could be per-
formed with aromatic substituted nitroalkenes containing
electron-donating groups, allowing the synthesis of com-
pound 5c in a good yield, good diastereomeric ratio and ac-
ceptable 72% ee (Table 2, entry 2). We have also found that
an electron-withdrawing group at the aromatic substituent
in the nitroalkene, such as a nitro group in the para-position,
reacts smoothly, providing 5d with good diastereoselectivity;
however, slighter lower yield and enantioselectivity were ob-
tained (Table 2, entry 3). The
moderate to high enantioselectivities (Table 3, entries 1, 2).
Bulkier R1 groups at C-4 in the oxazolone, such as iBu,
gave in one case a slightly lower diastereo- and enantiose-
lectivity compared with the other oxazolones studied
(Table 3, entry 3). Interestingly, the enantioselectivity in-
creased up to 82% ee when this reaction was carried out
with an o-Cl-C6H4 substituent at R2 and only one diastereo-
isomer could be detected (Table 3, entry 4). The later nucle-
ophile was additionally used for two different nitroalkenes,
p-MeOC6H4 and thiophen-2-yl derivatives (Table 3, en-
tries 5, 6). These reactions took placed in excellent yields,
enantioselectivities up to 90% ee and only one diastereoiso-
mer was obtained for both oxazolones.
reaction took also place with
Table 2. Scope of oxazolone 1b with nitroalkenes 2.[a]
heteroaromatic substituents as
thiophene with excellent yield,
good diastereomeric ratio and
enantioselectivity
(Table 2,
entry 4). An ortho-chloro sub-
stitution, as well as bulkier
groups, such as naphthyl could
be used obtaining the optically
active products 5 f and g with
similar good results (Table 2,
entries 5, 6). Interestingly, alkyl
chains in the nitroalkene could
also be applied, obtaining in all
the cases good yield, diastereo-
selectivity and slighter lower
Entry
R
Cat.
Yield [%][b]
dr[c]
ee [%][d]
83[e]
72
1
2
3
4
5
6
7
8
Ph
4c
4d
4c
4d
4c
4c
4b
4d
65 (5b)
90 (5c)
65 (5d)
91 (5e)
80 (5 f)
54 (5g)
88 (5h)
65 (5i)
>95:<5
93:7
81:19
91:9
92:8
>95:<5
95:5
>95:<5
p-MeO-C6H4
p-NO2-C6H4
thiophen-2-yl
o-Cl-C6H4
naphth-2-yl
Me
72
70[e]
74
66
66
67
MeSCH2CH2-
[a] Performed with 1 (0.20 mmol), 2 (0.20 mmol) and catalyst 4 (5 mol%) in toluene (0.2 mL). [b] Overall
yield. [c] Determined by 1H NMR. [d] Determined by chiral stationary phase HPLC. [e] ee was determined
enantioselectivity, exemplified after transformation into compound 6 (see Table 4).
10960
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a,a-Disubstituted a-Amino Acids
FULL PAPER
Table 3. Scope of different oxazolones 1a–h with nitroalkenes 2.[a]
conversion and the amino acid
esters 6a–e were obtained in
very high yields. This method is
compatible with oxazolones
with phenyl and alkyl group at
R1 (Table 4, entries 1, 2). The
reaction could also be carried
out with different substituents
at R2, such as electron-donating
groups (Table 4, entries 3, 4)
and bulkier groups as the naph-
thyl ring (Table 4, entry 5). In
these reaction, the correspond-
ing products 6a–e were ob-
tained without loss of enantio-
selectivity.
Entry
R1/R2
R3
Cat.
Yield [%][b]
dr[c]
91:9
93:7
80:20
>95:<5
>95:<5
>95:<5
>95:<5
>95:<5
95:5
>95:<5
>95:<5
>95:<5
>95:<5
ee [%][d]
1
2
3
4
5
6
7
Ph/p-Tol
Me/Ph
iBu/Ph
Ph
Ph
Ph
Ph
4c
4c
4c
4c
4d
4c
4d
4d
4d
4d
4d
4d
4d
98 (5a)
82 (5j)
93 (5k)
95 (5l)
82 (5m)
84 (5n)
93 (5o)
94 (5o)
91 (5p)
82 (5q)
85 (5r)
61 (5s)
64 (5t)
74
66
65
82
90
80
91
92
75
87
77
64
70
iBu/o-Cl-Ph
iBu/o-Cl-Ph
iBu/o-Cl-Ph
iBu/o-F-Ph
iBu/o-F-Ph
iBu/o-F-Ph
iBu/o-F-Ph
iBu/o-F-Ph
iBu/o-F-Ph
iBu/p-NO2-Ph
p-MeO-C6H4
2-thienyl
Ph
8[e]
9
10
11
12
13
Ph
p-NO2-Ph
2-thienyl
o-Cl-C6H4
2-Furyl
Ph
This reaction can also be car-
ried out as a one-pot procedure
by first the conjugate 1,4-addi-
tion of the oxazolone to the
[a] Performed with 1 (0.20 mmol), 2 (0.21 mmol) and catalyst 3 (5 mol%) in toluene (0.2 mL). [b] Overall
yield. [c] Determined by 1H NMR. [d] Determined by chiral stationary phase HPLC. [e] Reaction performed
at 2.0 mmol scale.
Encouraged by these results, we also introduced a fluorine
substituent in the ortho-position of a phenyl group at R2
(Table 3, entries 7–12). The o-F-C6H4 substituent had a posi-
tive influence on the enantioselectivity and in this case 91%
ee was obtained (Table 3, entry 7) compared to the o-Cl-
C6H4 substituent which gave 82% ee (Table 3, entry 4). We
have also shown that this reaction could be performed in
2 mmol scale giving an excellent diastereomeric ratio and a
slightly higher enantioselectivity (Table 3, entry 8). We then
Figure 1. X-ray structure of compound 5e.
explored different nitroalkenes for the reaction with the o-
F-C6H4-substituted oxazolone. For the nitroalkenes having a
p-NO2-C6H4 substituent (Table 3, entry 9), a heteroaromatic
group (Table 3, entry 10, 12), and o-Cl-C6H4 substituent
(Table 3, entry 11), the optically active addition products
were formed in all cases in good yields and excellent diaste-
reoselectivities and enantiomeric excesses from 64–87% ee.
Finally, we explored also the effect of an electron-withdraw-
ing group in the para-position of the phenyl substituent at
R2 in the oxazolone ring system. For this substrate having a
nitro substituent in the para-position, a slightly lower enan-
tioselectivity of the addition product 5t was obtained
(Table 3, entry 13) compared to the o-F- and o-Cl-C6H4 sub-
stituents (Table 3, entries 4, 7).
Table 4. Ring-opening reaction of oxazolones with TMSCl.[a]
Entry
Starting
material
R1
R2
Yield [%]
1
2
3
4
5
5a
5b
5c
5e
5g
Tol
tBu
tBu
tBu
tBu
Ph
Ph
99 (6a)
95 (6b)
87 (6c)
99 (6d)
99 (6e)
p-MeOC6H4
thiophene-2-yl
2-naphthyl
The absolute configuration of the two stereocenters was
determined as R,R by X-ray analysis of the crystals of com-
pound 5e (Figure 1).[19]
[a] Performed with 4 (0.20 mmol), and TMSCl (0.20 mmol) and 0.4 mL of
MeOH.
Transformations of the optically active products: One of our
objectives of this work was to develop new synthetic meth-
odologies for optically active a,a-quaternary a-amino acids
and their derivatives. Therefore, we decided to investigate
the ring-opening reactions of some of the optically active
oxazolone addition products 5a–c,e,g by using the protocol
developed by Trost et al.[16] (Table 4). This reaction was per-
formed with TMSCl in MeOH for 30 min with complete
nitroalkene catalyzed by 4c, followed by the direct addition
of TMSCl and MeOH. This one-pot procedure allows the
direct synthesis of a,a-quaternary amino acid derivatives
without loss of enantioselectivity compared with the two-
step procedure and 6b was formed in moderate isolated
yield (Scheme 3).
Furthermore, we were able to transform the optically
active oxazolones 5 to various compounds by using different
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K. A. Jørgensen et al.
13C NMR). 13C NMR spectra were acquired on a broad band decoupled
mode. Mass spectra were recorded on a Micromass LCT spectrometer
using electrospray (ES+) ionisation techniques. Analytical thin layer
chromatography (TLC) was performed using pre-coated aluminium-
backed plates (Merck Kieselgel 60 F254) and visualised by ultraviolet ir-
radiation or KMnO4 dip. Optical rotations were measured on a Perkin-
Elmer 241 polarimeter. The enantiomeric excess (ee) of the products was
determined by chiral stationary phase HPLC (Daicel Chiralpak AD or
Daicel Chiralcel OD, OJ columns).
Scheme 3. One-pot synthesis of optically active a,a-quaternary a-amino
acids.
Materials: Analytical grade solvents and nitroalkenes 2 were purchased
by Aldrich and used as received. Oxazolones were prepared according to
literature procedures. Flash chromatography (FC) was carried out using
Iatrobeads 6RS-8060 (spherical silica gel). Racemic samples were pre-
pared using DABCO as the catalyst. Catalyst 4a–d were obtained in two
step synthesis from cinchona commercial available catalyst.[18a]
strategies. Thus, compound 5b and h were transformed to
the corresponding amino-acid derivatives 7a and b with
conc. HCl in CH3CN in good yields (top, Scheme 4). The
nitro group in 5 could also be converted to the amine inter-
mediate by nickel boride reduction to give the 3,4-disubsti-
tuted pyrrolidin-2-one 8 by an intramolecular ring-opening
of the oxazolone intermediate (bottom, Scheme 4).
General procedure for the addition of oxazolones to nitroalkenes: An or-
dinary vial equipped with a magnetic stirring bar was charged with oxa-
zolone 1 (0.2 mmol) and the nitroalkene (0.2 mmol) in toluene (0.2 mL)
at À208C. After 15 min the corresponding catalyst 4 was added. The stir-
ring was maintained at À208C overnight and the crude reaction mixture
was directly charged onto Iatrobeads and subjected to FC.
(À)-4-(2-Nitro-1-phenylethyl)-4-phenyl-2-p-tolyloxazol-5(4H)-one (5a):
The title compound was obtained according to the general procedure
using 5 mol% of catalyst 4c after FC (hexane/Et2O 5:1) as a white solid
(72 mg, 90%). M.p. 129–1318C; [a]2D0 =À13.5 (c=0.3 in CH2Cl2);
1H NMR: d=7.79–7.73 (m, 4H), 7.42–7.10 (m, 10H), 5.00 (dd, J=13.2,
11.2, 1H), 4.46–4.37 (m, 2H), 2.35 ppm (s, 3H); 13C NMR: d=176.3,
161.5, 144.1, 135.6, 132.8, 129.6, 129.2, 129.1, 129.1, 128.8, 128.7, 128.0,
126.1, 122.3, 76.0, 75.4, 52.6, 21.7 ppm; HRMS: m/z: calcd for
C24H20N2NaO4: 423.1320; found 423.1317 [M+Na]+. The ee was deter-
mined by HPLC analysis using a Chiralpak AD column (hexane/iPrOH
80:20); flow rate 1.0 mLminÀ1; tminor =6.5 min, tmajor =16.8 min (74% ee).
(À)-2-tert-Butyl-4-(2-nitro-1-phenylethyl)-4-phenyloxazol-5(4H)-one
(5b): The title compound was obtained according to the general proce-
dure using 5 mol% of catalyst 4c after FC (hexane/Et2O 20:1) as a white
solid (48 mg, 65%). M.p. 97–998C; [a]2D0 =À52.1 (c=0.7 in CH2Cl2);
1H NMR: d=7.78 (d, J=7.2 Hz, 2H), 7.48–7.31 (m, 8H), 5.09 (td, J=
14.8, 4.4 Hz, 1H), 4.43–4.37 (m, 2H), 1.13 ppm (s, 9H); 13C NMR: d=
176.9, 171.4, 135.4, 132.7, 129.3 (2C), 128.9, 128.9, 128.5, 125.8, 125.7,
75.1, 74.9, 51.8, 34.1, 26.4 ppm; HRMS: m/z: calcd for C21H22N2NaO4:
389.1477; found 389.1487 [M+Na]+. The ee was determined after trans-
formation into the product 6b (83% ee).
Scheme 4. Different transformation of compounds 5.
Conclusion
(À)-2-tert-Butyl-4-[1-(4-methoxyphenyl)-2-nitroethyl]-4-phenyl
oxazol-
We have presented an easy and simple synthetic approach
to optically active a,a-quaternary a-amino acids using asym-
metric non-covalent organocatalysis. The addition of oxazo-
lones to nitroalkenes catalyzed by thiourea cinchona deriva-
tives achieved the corresponding a,a-quaternary a-amino
acid derivatives with good yields, excellent diastereoselecti-
vies, up to 98% dr, and from moderate to good enantiose-
lectivities, up to 92% ee. The reaction can be performed in
a large scale and the oxazolones could be opened in one-pot
reaction to the corresponding ester–amide derivatives. Addi-
tional transformations were also presented, such as synthesis
of synthesis of optically active amido esters, amido acids,
and 3,4-disubstituted pyrrolidin-2-ones.
5(4H)-one (5c): The title compound was obtained according to the gener-
al procedure using 5 mol% of catalyst 4d after FC (hexane/Et2O 9:1) as
a yellow oil (71 mg, 90%). [a]2D0 =À50.2 (c=0.9 in CH2Cl2); 1H NMR:
d=7.77–7.75 (m, 2H), 7.47–4.38 (m, 3H), 7.22 (d, J=8.8 Hz, 2H), 6.84
(d, J=8.8 Hz, 2H), 4.94 (dd, J=14.4, 12.4 Hz, 1H), 4.38–4.33 (m, 2H),
3.76 (s, 3H), 1.16 ppm (s, 9H); 13C NMR: d=177.1, 171.4 159.8, 135.5,
129.2, 125.8, 124.4, 113.9, 75.3, 75.2, 55.2, 51.3, 34.1, 26.4 ppm; HRMS:
m/z: calcd for C22H24N2NaO5: 419.1582; found 419.1582 [M+Na]+. The
ee was determined by HPLC analysis using a Chiralcel OD column
(hexane/iPrOH 90:10); flow rate 1.0 mLminÀ1; tminor =5.4 min, tmajor
6.4 min (72% ee).
=
(+)-2-tert-Butyl-4-[2-nitro-1-(4-nitrophenyl)ethyl]-4-phenyl
oxazol-
5(4H)-one (5d): The title compound was obtained according to the gen-
eral procedure using 5 mol% of catalyst 4c after FC (pentane/AcOEt
9:1) as a white solid (53 mg, 65%). M.p. 152–1538C; [a]2D0 =+63.4 (c=1.0
in CH2Cl2); 1H NMR: d=8.23–8.19 (m, 2H), 7.77–7.74 (m, 2H), 7.56–
7.41 (m, 4H), 5.01 (dd, J=13.9, 11.5 Hz, 1H), 4.51 (dd, J=11.5, 4.0 Hz,
1H), 4.43 (dd, J=14.0, 4.1 Hz, 2H), 1.16 ppm (s, 9H); 13C NMR: d=
176.4, 172.2, 148.1, 140.2, 134.6, 130.4, 129.7, 129.5, 125.7, 123.6, 74.6,
74.5, 51.3, 34.3, 26.5 ppm; HRMS: m/z: calcd for C21H21N3NaO6:
434.1328; found 434.1335 [M+Na]+. The ee was determined by HPLC
analysis using a Chiralcel OJ column (hexane/iPrOH 90:10); flow rate
1.0 mLminÀ1; tminor =22.6 min, tmajor =30.8 min (72% ee).
Experimental Section
General: NMR spectra were acquired on a Varian AS 400 spectrometer,
running at 400 and 100 MHz for 1H and 13C, respectively, at room tem-
perature. Chemical shifts (d) are reported in ppm relative to residual sol-
vent signals (CHCl3, 7.26 ppm for 1H NMR, CDCl3, 77.0 ppm for
(+)-2-tert-Butyl-4-[2-nitro-1-(thiophen-2-yl)ethyl]-4-phenyl
5(4H)-one (5e): The title compound was obtained according to the gen-
oxazol-
10962
www.chemeurj.org
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 10958 – 10966

a,a-Disubstituted a-Amino Acids
FULL PAPER
eral procedure using 5 mol% of catalyst 4d after FC (hexane/Et2O 15:1)
as an inseparable mixture of diastereoisomers (91:9) (68 mg, 91%). M.p.
110–1128C; [a]2D0 =+58.1 (c=1.0 in CH2Cl2); 1H NMR: d=7.76 (d, J=
7.2 Hz, 2H), 7.48–7.41 (m, 3H), 7.26 (d, J=5.2 Hz, 1H), 7.04 (d, J=
2.8 Hz, 1H), 6.96 (dd, J=8.8, 5.2 Hz, 1H), 4.86 (dd, J=13.2, 11.6 Hz,
1H), 4.75 (dd, J=12.0, 3.6 Hz, 1H), 4.40 (dd, J=13.7, 3.6 Hz, 1H),
1.22 ppm (s, 9H); 13C NMR: d=176.8, 172.3, 135.0 134.7, 129.3, 129.1,
128.6, 126.9, 126.1, 125.7, 76.5, 75.2, 47.6, 34.2, 26.3 ppm; HRMS: m/z:
calcd for C19H20N2NaO4S: 395.1041; found 395.1041 [M+Na]+. The ee
was determined after transformation into the product 6d (70% ee). Rep-
resentative 1H NMR signals of the minor diastereoisomer: d=7.70 (d,
J=5.2 Hz, 2H), 7.20 (d, J=4.8 Hz, 1H), 6.90 (dd, J=8.4, 4.8 Hz, 1H),
5.07 (dd, J=14.0, 12.4 Hz, 1H), 4.54–4.48 (m, 1H), 1.07 ppm (s, 9H).
129.5, 129.1, 128.7, 128.6, 125.9, 105.6, 74.9, 53.0, 13.4 ppm; HRMS: m/z:
calcd for C18H16N2NaO4: 347.1007; found 347.1011 [M+Na]+. The ee was
determined by HPLC analysis using a Chiralpak AD column (hexane/
iPrOH 90:10); flow rate 1.0 mLminÀ1
(66% ee).
; tminor =7.0 min, tmajor =9.0 min
(+)-4-Isobutyl-2-(2-nitro-1-phenylethyl)-2-phenyloxazol-5(2H)-one (5k):
The title compound was obtained according to the general procedure
using 5 mol% of catalyst 4c after FC (pentane/AcOEt 9:1) as a colorless
oil (68 mg, 93% as a mixture of diastereoisomers). [a]2D0 =+27.4 (c=0.5
1
in CH2Cl2); H NMR: d=7.67–7.61 (m, 2H), 7.44 (m, 3H), 7.37–7.16 (m,
5H), 4.92 (dd, J=13.3, 11.4 Hz, 1H), 4.60 (dd, J=13.5, 4.2 Hz, 1H), 4.45
(dd, J=11.1, 4.2 Hz, 1H), 2.21–2.08 (m, 2H), 1.85–1.73 (m, 1H), 0.69–
0.63 ppm (m, 6H); 13C NMR: d=164.7, 162.5, 136.2, 131.8, 129.6, 129.4,
129.0, 128.8, 128.8, 125.9, 105.8, 75.3, 52.9, 36.2, 26.1, 22.3, 22.1 ppm;
HRMS: m/z: calcd for C21H22N2NaO4: 389.1477; found 389.1480
[M+Na]+. The ee was determined by HPLC analysis using a Chiralpak
(À)-2-tert-Butyl-4-[1-(2-chlorophenyl)-2-nitroethyl]-4-phenyl
oxazol-
5(4H)-one (5 f): The title compound was obtained according to the gener-
al procedure using 5 mol% of catalyst 4c after FC (pentane/AcOEt 9:1)
as
a
colorless oil (64 mg, 80%). [a]2D0 =À41.2 (c=0.5 in CH2Cl2);
AD column (hexane/iPrOH 98:2); flow rate 1.0 mLminÀ1
10.1 min, tmajor =11.3 min (65% ee).
;
tminor
=
1H NMR: d=7.84–7.79 (m, 2H), 7.51–7.39 (m, 4H), 7.32 (dd, J=7.2,
2.3 Hz, 1H), 7.28–7.19 (m, 2H), 5.27 (dd, J=11.5, 3.9 Hz, 1H), 4.92 (dd,
J=13.7, 11.7 Hz, 1H), 4.48 (dd, J=13.9, 4.0 Hz, 1H), 1.25 ppm (s, 9H);
13C NMR: d=175.9, 171.9, 136.1, 135.7, 131.3, 130.7, 129.9, 129.3, 129.3,
128.3, 126.4, 125.9, 75.5, 74.6, 46.1, 34.2, 26.5 ppm; HRMS: m/z: calcd for
C21H21ClN2NaO4: 423.1088; found 423.1088 [M+Na]+. The ee was deter-
mined by HPLC analysis using a Chiralcel OD column (hexane/iPrOH
98:2); flow rate 1.0 mLminÀ1; tmajor =6.5 min, tminor =7.3 min (74% ee).
(+)-2-(2-Chlorophenyl)-4-isobutyl-2-(2-nitro-1-phenylethyl)
oxazol-
5(2H)-one (5l): The title compound was obtained according to the gener-
al procedure using 5 mol% of catalyst 4c after FC (pentane/AcOEt 9:1)
as
a
colorless oil (76 mg, 95%). [a]2D0 =+35.6 (c=0.5 in CH2Cl2);
1H NMR: d=7.53 (dd, J=9.4, 8.1 Hz, 2H), 7.35 (t, J=7.7 Hz, 1H), 7.32–
7.21 (m, 6H), 5.34 (dd, J=10.5, 4.4 Hz, 1H), 4.91 (dd, J=13.4, 10.7 Hz,
1H), 4.56 (dd, J=13.5, 4.5 Hz, 1H), 2.20–2.16 (m, 2H), 1.88–1.76 (m,
1H), 0.70 (d, J=6.8 Hz, 3H), 0.68 ppm (d, J=6.8 Hz, 3H); 13C NMR:
d=164.4, 163.6, 133.8, 132.6, 132.5, 132.2, 131.2, 129.7, 129.0, 128.5, 128.4,
127.5, 106.0, 75.6, 48.9, 36.4, 26.3, 22.5, 22.4 ppm; HRMS: m/z: calcd for
C21H21ClN2NaO4: 423.1088; found 423.1103 [M+Na]+. The ee was deter-
mined by HPLC analysis using a Chiralcel OD column (hexane/iPrOH
90:10); flow rate 1.0 mLminÀ1; tminor =10.2 min, tmajor =13.2 min (82%
ee).
(À)-2-tert-Butyl-4-[1-(naphthalen-2-yl)-2-nitroethyl]-4-phenyl
oxazol-
5(4H)-one (5g): The title compound was obtained according to the gen-
eral procedure using 5 mol% of catalyst 4c after FC (hexane/Et2O 15:1)
as a white solid (45 mg, 54%). M.p. 74–768C; [a]2D0 =À84.0 (c=0.5 in
CH2Cl2); 1H NMR: d=7.85–7.80 (m, 6H), 7.51–7.25 (m, 6H), 5.15 (dd,
J=13.6 11.6 Hz, 1H), 4.60 (dd, J=11.6, 4 Hz, 1H), 4.49 (dd, J=13.6,
4.0 Hz, 1H), 1.07 ppm (s, 9H); 13C NMR: d=176.9, 171.5, 135.4, 133.2,
132.7, 130.2, 129.3, 129.2, 128.8 (2C), 128.3, 127.9, 127.6, 126.6, 126.5,
125.8, 75.2 (2C), 51.9, 34.1, 26.3 ppm; HRMS: m/z: calcd for
C25H24N2NaO4: 439.1633; found 439.1636 [M+Na]+. The ee was deter-
mined by HPLC analysis using a Chiralpak AD column (hexane/iPrOH
90:10); flow rate 1.0 mLminÀ1; tmajor =5.4 min, tminor =5.9 min (66% ee).
(À)-2-(2-Chlorophenyl)-4-isobutyl-2-[1-(4-methoxyphenyl)-2-nitroethy-
l]oxazol-5(2H)-one (5m): The title compound was obtained according to
the general procedure using 5 mol% of catalyst 4d after (pentane/
AcOEt 9:1) as a colorless oil (70 mg, 82%). [a]2D0 =À21.4 (c=0.5 in
CH2Cl2); 1H NMR: d=7.57–7.50 (m, 2H), 7.35 (td, J=7.9, 1.7 Hz, 1H),
7.31–7.25 (m, 1H), 7.16 (d, J=8.7 Hz, 2H), 6.80 (d, J=8.8 Hz, 2H), 5.28
(dd, J=10.7, 4.5 Hz, 1H), 4.85 (dd, J=13.2, 10.8 Hz, 1H), 4.52 (dd, J=
13.3, 4.5 Hz, 1H), 3.75 (s, 3H), 2.22–2.18 (m, 2H), 1.92–1.80 (m, 1H),
0.72 (d, J=6.8 Hz, 3H), 0.70 ppm (d, J=6.7 Hz, 3H); 13C NMR: d=
164.1, 163.3, 159.7, 133.6, 132.5, 132.2, 130.9, 130.6, 128.2, 127.3, 123.6,
114.1, 105.9, 75.6, 55.1, 47.9, 36.2, 26.1, 22.3, 22.1 ppm; HRMS: m/z: calcd
for C22H23ClN2NaO5: 453.1193; found 453.1194 [M+Na]+. The ee was de-
termined by HPLC analysis using a Chiralpak AD column (hexane/
iPrOH 90:10); flow rate 1.0 mLminÀ1; tmajor =8.6 min, tminor =14.0 min
(90% ee).
(+)-2-tert-Butyl-4-(1-nitropropan-2-yl)-4-phenyloxazol-5(4H)-one (5h):
The title compound was obtained according to the general procedure
using 5 mol% of catalyst 4b after FC (pentane/AcOEt 9:1) as a white
solid (53 mg, 88%). M.p. 150–1528C; [a]2D0 =+46.7 (c=1.0 in CH2Cl2);
1H NMR: d=7.61 (d, J=8.1 Hz, 2H), 7.46–7.34 (m, 3H), 4.27 (dd, J=
12.7, 10.7 Hz, 1H), 4.18 (dd, J=12.8, 3.5 Hz, 1H), 3.30–3.20 (m, 1H),
1.35 (s, 9H), 0.99 ppm (d, J=6.6 Hz, 3H); 13C NMR: d=177.8, 172.0,
135.6, 129.1, 129.0, 125.6, 77.1, 74.6, 40.8, 34.5, 26.9, 12.7 ppm; HRMS:
m/z: calcd for C16H20N2NaO4: 327.1321; found 327.1307 [M+Na]+. The
ee was determined by HPLC analysis using a Chiralcel OJ column
(hexane/iPrOH 90:10); flow rate 1.0 mLminÀ1; tminor =5.0 min, tmajor
5.8 min (66% ee).
=
(+)-2-(2-Chlorophenyl)-4-isobutyl-2-[2-nitro-1-(thiophen-2-yl)ethyl]oxa-
zol-5(2H)-one (5n): The title compound was obtained according to the
general procedure using 5 mol% of catalyst 4c after FC (pentane/AcOEt
9:1) as a colorless oil (68 mg, 84%). [a]2D0 =+29.5 (c=0.2 in CH2Cl2);
1H NMR: d=7.55 (ddd, J=15.6, 7.9, 1.5 Hz, 2H), 7.37 (td, J=7.9, 1.7 Hz,
1H), 7.29 (td, J=7.7, 1.3 Hz, 1H), 7.23 (dd, J=5.1, 1.0 Hz, 1H), 6.98 (dd,
J=3.7, 1.0 Hz, 1H), 6.92 (dd, J=5.1, 3.5 Hz, 1H), 5.65 (dd, J=10.5,
4.3 Hz, 1H), 4.77 (dd, J=13.3, 10.5 Hz, 1H), 4.55 (dd, J=13.3, 4.3 Hz,
1H), 2.33–2.21 (m, 2H), 1.98–1.88 (m, 1H), 0.78–0.75 ppm (m, 6H);
13C NMR: d=164.1, 163.5, 133.6, 133.2, 132.4, 132.2, 131.1, 128.8, 128.2,
127.3, 127.1, 126.7, 105.2, 76.7, 44.4, 36.3, 26.1, 22.2, 22.2 ppm; HRMS:
m/z: calcd for C19H19ClN2NaO4: 429.0652; found 429.0645 [M+Na]+. The
ee was determined by HPLC analysis using a Chiralpak AD column
(+)-2-tert-Butyl-4-[4-(methylthio)-1-nitrobutan-2-yl]-4-phenyl
oxazol-
5(4H)-one (5i): The title compound was obtained according to the gener-
al procedure using 5 mol% of catalyst 4d after FC (pentane/AcOEt 9:1)
as
a
colorless oil (47 mg, 65%). [a]2D0 =+61.3 (c=1.0 in CH2Cl2);
1H NMR: d=7.62–7.60 (m, 2H), 7.45–7.35 (m, 3H), 4.32 (dd, J=8.4,
5.7 Hz, 2H), 3.40–3.26 (m, 1H), 2.61–2.43 (m, 2H), 2.05 (s, 3H), 1.66–
1.60 (m, 2H), 1.34 ppm (s, 9H); 13C NMR: d=177.9, 171.8, 135.5, 129.1,
129.0, 125.9, 75.3, 75.0, 44.3, 44.3, 34.4, 31.1, 28.2, 26.8 ppm; HRMS: m/z:
calcd for C18H24N2NaO4S: 387.1354; found 387.1357 [M+Na]+. The ee
was determined by HPLC analysis using
a
Chiralpak AD column
tminor =6.8 min, tmajor =
(hexane/iPrOH 98:2); flow rate 1.0 mLminÀ1
7.5 min (67% ee).
;
(hexane/iPrOH 90:10); flow rate 1.0 mLmin; tminor =8.1 minÀ1, tmajor
10.8 min (80% ee).
=
(+)-4-Methyl-2-(2-nitro-1-phenylethyl)-2-phenyloxazol-5(2H)-one (5j):
The title compound was obtained according to the general procedure
using 5 mol% of catalyst 4c after FC (hexane/Et2O 5:1) as a white solid
(53 mg, 82%). M.p. 150–1528C; [a]2D0 =+50.0 (c=0.4 in CH2Cl2);
1H NMR: d=7.63–7.61 (m, 2H), 7.46–7.27 (m, 8H), 4.93 (dd, J=13.3,
11.2 Hz, 1H), 4.59 (dd, J=13.6, 4.4 Hz, 1H), 4.43 (dd, J=11.2, 4.4 Hz,
1H), 1.90 ppm (s, 3H); 13C NMR: d=164.5, 160.1, 135.7, 131.5, 129.7,
(À)-2-(2-Fluorophenyl)-4-isobutyl-2-(2-nitro-1-phenylethyl)oxazol-5(2H)-
one (5o): The title compound was obtained according to the general pro-
cedure using 5 mol% of catalyst 4d after FC (pentane/AcOEt 9:1) as a
colorless oil (71 mg, 93%). [a]2D0 =À38.2 (c=1.0 in CH2Cl2); 1H NMR:
d=7.22 (m, 9H), 4.96–4.83 (m, 2H), 4.61 (dd, J=12.5, 3.6 Hz, 1H), 2.23–
2.09 (m, 2H), 1.84–1.72 (m, 1H), 0.66 (d, J=6.7 Hz, 3H), 0.63 ppm (d,
Chem. Eur. J. 2008, 14, 10958 – 10966
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10963

K. A. Jørgensen et al.
J=6.7 Hz, 3H); 13C NMR: d=164.4, 163.4, 159.4 (d, J
131.9 (d, J(C,F) = 8.5 Hz), 131.8, 129.5, 128.8, 127.3 (d, J
124.6 (d, J(C,F)=3.6 Hz), 123.5 (d, J(C,F)=11.1 Hz), 117.2 (d, J
22.1 Hz), 104.5 (d, J(C,F)=6.1 Hz), 75.5, 50.3, 50.2, 36.2, 26.2, 22.3,
G
iPrOH 90:10); flow rate 1.0 mLminÀ1
(64% ee).
;
tmajor =7.2 min, tminor =9.0 min
G
ACHTUNGTRENNUNG
E
U
ACHTUNGTRENNUNG
(À)-4-Isobutyl-2-(2-nitro-1-phenylethyl)-2-(4-nitrophenyl)oxazol-5(2H)-
one (5t): The title compound was obtained according to the general pro-
cedure using 5 mol% of catalyst 4d after FC (pentane/AcOEt 9:1) as a
white solid (53 mg, 64%). M.p. 129–1338C; [a]2D0 =À35.6 (c=1.0 in
CH2Cl2); 1H NMR: d=8.32–8.26 (m, 2H), 7.82–7.77 (m, 2H), 7.34–7.28
(m, 3H), 7.13–7.15 (m, 2H), 4.87 (dd, J=13.4, 10.3 Hz, 1H), 4.58 (dd, J=
13.5, 4.8 Hz, 1H), 4.43 (dd, J=10.3, 4.9 Hz, 1H), 2.26–2.15 (m, 2H), 1.85
(sept, J=6.4 Hz, 1H), 0.72 (d, J=6.7 Hz, 3H), 0.69 ppm (d, J=6.7 Hz,
3H); 13C NMR: d=163.9, 163.8, 148.4, 142.8, 131.3, 129.4, 129.1, 128.9,
127.4, 124.0, 105.0, 74.9, 52.7, 36.3, 26.0, 22.3, 22.1 ppm; HRMS: m/z:
C21H21N3NaO6: 434.1328; found 434.1301 [M+Na]+. The ee was deter-
mined by HPLC analysis using a Chiralpak AD column (hexane/iPrOH
90:10); flow rate 1.0 mLminÀ1; tmajor =14.2 min, tminor =18.5 min (70%
ee).
General procedure for the ring opening of oxazolones with TMSCl:[16a]
An ordinary vial equipped with a magnetic stirring bar was charged with
MeOH (0.20 mL) and the corresponding oxazolone 5 (0.1 mmol). Then,
TMSCl (0.1 mmol) was added in one portion. The stirring was main-
tained at room temperature until consumption of the starting material.
Then, the solvent was evaporated and the product was obtaining pure
without further purification.
ACHTUNGTRENNUNG
22.1 ppm; HRMS: m/z: calcd for C21H21FN2NaO4: 407.1383; found
407.1399 [M+Na]+. The ee was determined by HPLC analysis using a
Chiralcel OD column (hexane/iPrOH 90:10); flow rate 1.0 mLminÀ1
tmajor =9.8 min, tminor =12.0 min, (92% ee).
;
(À)-2-(2-Fluorophenyl)-4-isobutyl-2-[2-nitro-1-(4-nitrophenyl)ethyl]oxa-
zol-5(2H)-one (5p): The title compound was obtained according to the
general procedure using 5 mol% of catalyst 4d after FC (pentane/AcOEt
9:1) as a colorless oil (78 mg, 91%). [a]2D0 =À31.0 (c=1.0 in CH2Cl2);
1H NMR: d=8.15 (d, J=8.8 Hz, 2H), 7.51–7.41 (m, 3H), 7.38 (td, J=7.7,
1.6 Hz, 1H), 7.22 (ddd, J=11.3, 8.3, 0.9 Hz, 1H), 7.16 (td, J=7.7, 1.0 Hz,
1H), 5.00–4.88 (m, 2H), 4.65 (dd, J=13.2, 3.7 Hz, 1H), 2.33–2.19 (m,
2H), 1.94–1.82 (m, 1H), 0.71 (d, J=6.7 Hz, 3H), 0.68 ppm (d, J=6.7 Hz,
3H); 13C NMR: d=164.2, 163.8, 159.3 (d,
139.5, 132.3 (d, J(C,F)=8.0 Hz), 130.6, 127.3, 124.8 (d, J
123.8, 123.0 (d, J(C,F)=11.1 Hz), 117.3 (d, J(C,F)=22.0 Hz), 104.0 (d,
(C,F)=5.9 Hz), 74.9, 49.9, 36.3, 26.2, 22.2, 22.0 ppm; HRMS: m/z: calcd
JACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
JACHTUNGTRENNUNG
for C21H20FN3NaO6: 452.1234; found 452.1248 [M+Na]+. The ee was de-
termined by HPLC analysis using a Chiralpak AD column (hexane/
iPrOH 95:5); flow rate 1.0 mLminÀ1; tmajor =17.2 min, tminor =22.4 min
(75% ee).
(+)-Methyl 2-(4-methylbenzamido)-4-nitro-2,3-diphenylbutanoate (6a):
The title compound was obtained according to the general procedure
starting from 5a as a colorless oil (43 mg, 99%). [a]2D0 =+4.8 (c=1.0 in
CH2Cl2); 1H NMR: d=7.72 (d, J=8.0 Hz, 2H), 7.56 (d, J=7.6 Hz, 1H),
7.43 (t, J=7.2 Hz, 1H), 7.38–7.20 (m, 5H), 5.33 (dd, J=14.0, 2.4 Hz,
1H), 5.24 (dd, J=11.2, 2.0 Hz, 1H), 5.01 (dd, J=14.0, 11.6 Hz, 1H), 3.66
(s, 3H), 2.44 ppm (s, 3H); 13C NMR: d=171.5, 166.3, 142.8, 135.1, 134.7,
130.9, 127.5, 129.3, 129.2, 128.7, 128.5, 127.1, 126.2, 77.9, 53.9, 49.1,
21.5 ppm; HRMS: m/z: calcd for C25H24N2NaO5: 455.1582; found
455.1570 [M+Na]+. The ee was determined by HPLC analysis using a
Chiralcel OD column (hexane/iPrOH 90:10); flow rate 1.0 mLminÀ;
tminor =8.9 min, tmajor =10.9 min (74% ee).
(À)-2-(2-Fluorophenyl)-4-isobutyl-2-[2-nitro-1-(thiophen-2-yl)ethyl]oxa-
zol-5(2H)-one (5q): The title compound was obtained according to the
general procedure using 5 mol% of catalyst 4d after FC (pentane/AcOEt
9:1) as a colorless oil (64 mg, 82%). [a]2D0 =À31.6 (c=1.0 in CH2Cl2);
1H NMR: d=7.51–7.41 (m, 2H), 7.25–7.13 (m, 3H), 6.98 (dd, J=3.6,
1.1 Hz, 1H), 6.92 (dd, J=5.1, 3.5 Hz, 1H), 5.19 (dd, J=10.7, 4.2 Hz, 1H),
4.80 (ddd, J=13.3, 10.7, 0.6 Hz, 1H), 4.61 (dd, J=13.4, 4.2 Hz, 1H), 2.26
(dd, J=7.0, 0.8 Hz, 2H), 1.96–1.84 (m, 1H), 0.70–0.66 ppm (m, 6H);
13C NMR: d=164.4, 163.6, 159.5 (d, J
ACHTUNGTRENNUNG
J
J
N
ACHTUNGTRENNUNG
G
ACHTUNGTRENNUNG
104.0 (d, JACHTUNGTRENNUNG(C,F)=6.3 Hz), 76.8, 45.8, 36.3, 26.2, 22.2 ppm (2C); HRMS:
(À)-Methyl 4-nitro-2,3-diphenyl-2-(pivalamido)butanoate (6b): The title
compound was obtained according to the general procedure starting
from 5b as a white solid (38 mg, 95%). M.p. 72–758C; [a]2D0 =À10.0 (c=
0.2 in CH2Cl2); 1H NMR: d=7.35–7.12 (m, 10H), 7.08 (brs, 1H), 5.16
(dd, J=16.4, 2.4 Hz, 1H), 5.04 (dd, J=11.6, 2.8 Hz, 1H), 4.75 (dd, J=
14.0, 11.6 Hz, 1H), 3.56 (s, 3H), 1.20 ppm (s, 9H); 13C NMR: d=177.5,
171.6, 135.3, 134.7, 129.3, 129.1, 128.7, 128.6, 128.5, 125.8, 77.7, 67.7, 53.6,
48.5, 39.4, 27.5 ppm; HRMS: m/z: calcd for C22H26N2NaO5: 421.1739;
found 421.1737 [M+Na]+. The ee was determined by HPLC analysis
m/z: calcd for C19H19FN2NaO4S: 413.0947; found 413.0959 [M+Na]+. The
ee was determined by HPLC analysis using a Chiralcel OD column
(hexane/iPrOH 95:5); flow rate 1.0 mLminÀ1; tmajor =10.3 min, tminor
11.7 min (87% ee).
=
(À)-2-[1-(2-Chlorophenyl)-2-nitroethyl]-2-(2-fluorophenyl)-4-isobutyloxa-
zol-5(2H)-one (5r): The title compound was obtained according to the
general procedure using 5 mol% of catalyst 4d after FC (pentane/AcOEt
9:1) as a colorless oil (71 mg, 85%). [a]2D0 =À36.0 (c=1.0 in CH2Cl2);
1H NMR: d=7.55–7.15 (m, 8H), 5.70 (dd, J=10.8, 4.3 Hz, 1H), 4.91 (dd,
J=13.6, 11.0 Hz, 1H), 4.68 (dd, J=13.8, 4.4 Hz, 1H), 2.26–2.12 (m, 2H),
1.85–1.73 (m, 1H), 0.68 (d, J=6.7 Hz, 3H), 0.63 ppm (d, J=6.7 Hz, 3H);
using
a Chiralcel OD column (hexane/iPrOH 90:10); flow rate
1.0 mLminÀ1; tmajor =6.5 min, tminor =7.5 min (83% ee).
(À)-Methyl
3-(4-methoxyphenyl)-4-nitro-2-phenyl-2-(pivalamido)buta-
noate (6c): The title compound was obtained according to the general
13C NMR: d=164.4, 163.6, 159.5 (d, J
(C,F)=8.6 Hz), 130.5, 130.1, 129.9, 128.3, 127.4 (d, J
127.1, 124.6 (d, J(C,F)=3.7 Hz), 123.1 (d, J(C,F)=11.1 Hz), 117.4 (d,
(C,F)=22.0 Hz), 104.7 (d, J(C,F)=5.9 Hz), 75.4, 45.3, 36.2, 26.3, 22.1,
ACHTUNGTRENNUNG
procedure starting from 5c as a colorless oil (37 mg, 87%). [a]2D0 =À1.3
J
N
ACHTUNGTRENNUNG
1
A
ACHTUNGTRENNUNG
(c=0.7 in CH2Cl2); H NMR: d=7.42–7.35 (m, 5H), 7.17 (brs, 1H), 7.10
J
N
ACHTUNGTRENNUNG
(d, J=8.8 Hz, 2H), 6.84 (d, J=8.8 Hz, 2H), 5.20 (dd, J=14.0, 2.4 Hz,
1H), 5.08 (dd, J=12.0, 2.4 Hz, 1H), 4.78 (dd, J=14.0, 12.0 Hz, 1H), 3.79
(s, 3H), 3.63 (s, 3H), 1.29 ppm (s, 9H); 13C NMR: d=177.4, 171.7, 159.6,
135.4, 130.3, 129.0, 128.4, 126.4, 125.8, 113.9, 77.9, 67.8, 55.2, 53.7, 47.9,
39.4, 27.5 ppm; HRMS: m/z: calcd for C23H28N2NaO6: 451.1845; found
451.1840 [M+Na]+. The ee was determined by HPLC analysis using a
22.0 ppm; MS: calcd for C21H20ClFN2NaO4: 441.0993; found 441.1004
[M+Na]+. The ee was determined by HPLC analysis using a Chiralpak
AD column (hexane/iPrOH 95:5); flow rate 1.0 mLminÀ1; tminor =8.7 min,
tmajor =10.0 min (77% ee).
(À)-2-(2-Fluorophenyl)-2-[1-(furan-2-yl)-2-nitroethyl]-4-isobutyl oxazol-
5(2H)-one (5s): The title compound was obtained according to the gener-
al procedure using 5 mol% of catalyst 4d after FC (pentane/AcOEt 9:1)
Chiralcel OD column (hexane/iPrOH 90:10); flow rate 1.0 mLminÀ1
;
tminor =8.6 min, tmajor =10.1 min (58% ee, starting from a sample of 58%
ee).
as
a
colorless oil (46 mg, 61%). [a]2D0 =À25.6 (c=1.0 in CH2Cl2);
1H NMR: d=7.51–7.42 (m, 2H), 7.33 (brs, 1H), 7.26–7.17 (m, 2H), 6.28
(brs, 2H), 5.00 (dd, J=10.7, 3.7 Hz, 1H), 4.87 (dd, J=13.5, 10.7 Hz, 1H),
4.56 (dd, J=13.5, 3.9 Hz, 1H), 2.34–2.24 (m, 2H), 1.95 (sept, J=6.8 Hz,
1H), 0.83–0.79 ppm (m, 6H); 13C NMR: d=164.2, 163.5, 159.5 (d,
(+)-Methyl 4-nitro-2-phenyl-2-(pivalamido)-3-(thiophen-2-yl)butanoate
(6d): The title compound was obtained according to the general proce-
dure starting from 5e as a white solid (40 mg, 99%). M.p. 150–1538C;
[a]2D0 =+40.7 (c=0.3 in CH2Cl2); 1H NMR: d=7.43–7.25 (m, 7H), 6.50
(dd, J=4.8, 3.6 Hz, 1H), 6.91 (d, J=2.8 Hz, 1H), 5.49 (dd, J=11.2,
2.0 Hz, 1H), 5.22 (dd, J=14.0, 2.0 Hz, 1H), 4.68 (dd, J=13.6, 11.6 Hz,
1H), 3.62 (s, 3H), 1.31 ppm (s, 9H); 13C NMR: d=177.8, 171.7, 137.2,
135.0, 129.5, 128.8, 128.6, 126.8, 126.7, 125.9, 79.7, 67.9, 54.2, 45.6, 39.7,
27.7 ppm; HRMS: m/z: calcd for C20H24N2NaO5S: 427.1303; found
J
N
N
ACHTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
22.0 Hz), 111.1, 110.6, 104.0, 74.2, 44.6, 36.3, 26.0, 22.4, 22.2 ppm; HRMS:
m/z: C19H19FN2NaO5: 397.1176; found 397.1165 [M+Na]+. The ee was
determined by HPLC analysis using a Chiralpak AD column (hexane/
10964
www.chemeurj.org
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 10958 – 10966

a,a-Disubstituted a-Amino Acids
FULL PAPER
427.1302 [M+Na]+. The ee was determined by HPLC analysis using a
Chiralcel OD column (hexane/iPrOH 98:2); flow rate 1.0 mLminÀ1
tmajor =9.5 min, tminor =10.7 min (70% ee).
;
[1] For recent reviews on organocatalysis, see e.g.: a) P. I. Dalko, L.
Moisan, Angew. Chem. 2004, 116, 5248; Angew. Chem. Int. Ed. 2004,
43, 5138; b) A. Berkessel, H. Grçger, Asymmetric Organocatalysis,
VCH, Weinheim, 2004; c) Special issue No. 8 on organocatalysis
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A. McNally, N. C. Vo, Drug Discovery Today 2007, 12, 8; h) P. I.
Dalko, Enantioselective Organocatalysis, Wiley-VCH, Weinheim,
2007; i) Special issue No. 12 on organocatalysis Chem. Rev. 2007,
107: j) S. E. Denmark, G. L. Beutner, Angew. Chem. 2008, 120, 1584;
Angew. Chem. Int. Ed. 2008, 47, 1560; k) A. Dondoni, A. Massi,
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Int. Ed. 2008, 47, 6138; m) X. Xu, W. Wang, Org. Biomol. Chem.
2008, 6, 2037.
(+)-Methyl 3-(naphthalen-2-yl)-4-nitro-2-phenyl-2-(pivalamido)butanoate
(6e): The title compound was obtained according to the general proce-
dure starting from 5g (44 mg, 99%). M.p. 60–638C; [a]2D0 =+6.0 (c=0.3
1
in CH2Cl2); H NMR: d=7.84–7.65 (m, 4H), 7.51–7.39 (m, 7H), 7.29 (dd,
J=8.8, 1.6 Hz, 1H), 7.15 (brs, 1H), 5.35–5.30 (m, 2H), 4.98 (dd, J=14.4,
12.0 Hz, 1H), 3.65 (s, 3H), 1.30 ppm (s, 9H); 13C NMR: d=177.6, 171.6,
135.3, 133.1, 132.9, 132.2, 129.1, 128.9, 128.6, 128.3, 127.8, 127.6, 126.6,
126.5, 125.9, 77.8, 53.7, 48.6, 39.4, 27.5 ppm; HRMS: m/z: calcd for
C25H24N2NaO5: 471.1895; found 471.1879 [M+Na]+. The ee was deter-
mined by HPLC analysis using a Chiralcel OD column (hexane/iPrOH
90:10); flow rate 1.0 mLminÀ1; tmajor =10.6 min, tminor =15.2 min (66%
ee).
General procedure for the ring opening of the oxazolones with HCl: An
ordinary vial equipped with a magnetic stirring bar was charged with
CH3CN (0.30 mL) and the corresponding oxazolone 5 (0.1 mmol). Then,
HCl conc. (0.5 mmol) was added in one portion. The stirring was main-
tained at room temperature until consumption of the starting material.
Then, the solvent was evaporated and the crude reaction mixture was di-
rectly charged onto Iatrobeads and subjected to FC.
[2] For general reviews of organocatalytic conjugate addition, see:
a) S. B. Tsogoeva, Eur. J. Org. Chem. 2007, 1701; b) D. Almasi,
D. A. Alonso, C. Nꢀjera, Tetrahedron: Asymmetry 2007, 18, 299;
c) J. L. Vicario, D. Badꢄa, L. Carrillo, Synthesis 2007, 2065.
[3] For recent reviews on conjugated additions using iminium-ion acti-
vation see e.g.: a) S. B. Tsogoeva, Eur. J. Org. Chem. 2007, 1701;
b) D. Almasi, D. A. Alonso, C. Najera, Tetrahedron: Asymmetry
2007, 18, 299. For examples see e.g.: c) K. A. Ahrendt, C. J. Borths,
D. W. C. MacMillan, J. Am. Chem. Soc. 2000, 122, 4243; d) M.
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zꢅn, M. Marigo, K. A. Jørgensen, Angew. Chem. 2006, 118, 4411;
Angew. Chem. Int. Ed. 2006, 45, 4305; f) H. Gotoh, R. Masui, H.
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Chem. Int. Ed. 2006, 45, 6853; g) S. Mayer, B. List, Angew. Chem.
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H. Li, J. Wang, L. Zu, J. Am. Chem. Soc. 2006, 128, 10354; i) R.
Rios, H. Sundꢅn, I. Ibrahem, G. Zhao, L. Eriksson, A. Cꢂrdova, Tet-
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gensen, J. Am. Chem. Soc. 2006, 128, 14986; k) Y. K. Chen, M. Yosh-
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Ibrahem, R. Rios, J. Vesely, G. Zhao, A. Cꢂrdova, Chem. Commun.
2007, 849; m) J. Vesely, I. Ibrahem, G. Zhao, R. Rios, A. Cꢂrdova,
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n) S. Bertelsen, P. Dinꢅr, R. L. Johansen, K. A. Jørgensen, J. Am.
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K. A. Jørgensen, Angew. Chem. 2007, 119, 2029; Angew. Chem. Int.
Ed. 2007, 46, 1983; p) A. Carlone, G. Bartoli, M. Bosco, L. Sambri,
P. Melchiorre, Angew. Chem. 2007, 119, 4588; Angew. Chem. Int.
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H. Sundꢅn, P. Dziedzic, A. Cꢂrdova, Chem. Eur. J. 2008, 14, 7867.
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(+)-3-Methyl-4-nitro-2-phenyl-2-pivalamidobutanoic acid (7a): The title
compound was obtained according to the general procedure after FC
(pentane/AcOEt 2:1) as a white solid (23 mg, 70%). M.p. 146–1508C;
1
[a]2D0 =+41.7 (c=1.0 in CH2Cl2); H NMR: d=10.55 (brs, 1H), 7.52–7.27
(m, 5H), 4.77 (dd, J=13.6, 2.0 Hz, 1H), 4.26–4.00 (m, 1H), 3.66–3.53 (m,
1H), 1.25 (s, 9H), 1.06 ppm (d, J=6.7 Hz, 3H); 13C NMR: d=179.8,
173.2, 135.0, 128.9, 128.6, 125.7, 79.6, 68.6, 39.5, 39.2, 27.3, 14.5 ppm;
HRMS: m/z: calcd for C16H21N2NaO5: 345.1426; found 345.1415
[M+Na]+.
(À)-4-Nitro-2,3-diphenyl-2-(pivaloyl)butanoic acid (7b): The title com-
pound was obtained according to the general procedure after FC (pen-
tane/AcOEt 2:1) as a white solid (32 mg, 84%). M.p. 169–1738C; [a]D20
=
À29.3 (c=1.0 in EtOAc); 1H NMR: d=7.49–7.27 (m, 8H), 7.17–7.15 (m,
2H), 7.03 (brs, 1H), 5.15 (dd, J=13.8, 2.3 Hz, 1H), 5.06–4.92 (m, 1H),
4.69 (t, J=12.6 Hz, 1H), 1.17 ppm (s, 9H); 13C NMR: d=179.2, 172.5,
134.4, 134.1, 129.6, 128.9, 128.8, 128.7, 128.7, 126.2, 77.4, 67.6, 48.5, 39.4,
27.3 ppm; HRMS: m/z: calcd for C21H24N2NaO5: 407.1583; found
407.1579 [M+Na]+.
(+)-N-(2-Oxo-3,4-diphenylpyrrolidin-3-yl)pivalamide (8): To a solution
of 5b (20 mg, 0.05 mmol) and NiCl2·6H2O (12 mg, 0.05 mmol) in EtOH
(0.5 mL) was added NaBH4 (19 mg, 0.5 mmol) at room temperature. The
reaction was stirred for 2 h before quenched with sat. aq. solution of
NH4Cl (5 mL). The reaction was extracted with CH2Cl2 (2ꢃ5mL), the or-
ganic layer was dried over MgSO4 and filtered though a pad of Celite-Ia-
trobeads. The solvent was eliminated in vacuo to afford 8 (12 mg, 72%).
1
[a]2D0 =+8.8 (c=0.5 in CH2Cl2); H NMR: d=7.19–7.03 (m, 6H), 6.72 (d,
J=8.0 Hz, 2H), 6.59 (d, J=7.2 Hz, 2H), 6.28 (brs, 1H), 5.98 (brs, 1H),
4.94 (dd, J=10.4, 8.0 Hz, 1H), 3.60 (d, J=8.4 Hz, 1H), 3.45 (d, J=
10.4 Hz, 1H), 1.23 ppm (s, 9H); 13C NMR: d=179.1, 174.5, 136.1, 135.4,
129.0, 128.6, 128.4, 127.9, 127.4, 126.4, 126.3, 77.2, 47.8, 42.2, 39.1, 29.7,
27.5 ppm; HRMS: m/z: calcd for C21H24N2NaO2: 359.1735; found
359.1730 [M+Na]+.
Acknowledgements
This work was made possible by a grant from Danish National Research
Foundation and OChemSchool. S.C. and J.A. thank the Ministerio de Ed-
ucaciꢂn y Ciencia of Spain and E.R. thanks the “Eusko Jaurlaritza-Go-
bierno Vasco” for their post-doctoral fellowships. Thanks are expressed
to Dr. Jacob Overgaard for performing X-ray analysis.
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ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10965

K. A. Jørgensen et al.
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Please note: Minor changes have been made to the formulae in Table 3
in this manuscript since its publication in Chemistry–A European Journal
Early View. The Editor.
Received: October 2, 2008
Published online: October 31, 2008
10966
www.chemeurj.org
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Chem. Eur. J. 2008, 14, 10958 – 10966