SupraBox: Chiral supramolecular oxazoline ligands

Article abstract of DOI:10.1002/ejoc.201200516

A new class of oxazoline ligands, named SupraBox, was studied. These ligands possess an additional urea functionality to generate supramolecular bidentate ligands in transition-metal complexes, by the establishment of hydrogen bonds between the urea N-hydrogens of one ligand and the carbonyl oxygen of a second one. A library of 16 SupraBox ligands was prepared using 5 differently substituted oxazoline nuclei, 4 linkers and 3 different urea substituents. The formation of copper(II) and palladium(II) complexes was investigated by MS, UV/Vis and ¹H-NMR spectroscopy. The SupraBox library was screened in the copper-catalyzed asymmetric benzoylation of vic-diols. Good selectivities were obtained in the kinetic resolution of racemic hydrobenzoin [up to 86 % ee and selectivity (s) = 28] and in the desymmetrization of meso-hydrobenzoin (up to 88 % ee).

Full text of DOI:10.1002/ejoc.201200516

Job/Unit: O20516
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FULL PAPER
DOI: 10.1002/ejoc.201200516
SupraBox: Chiral Supramolecular Oxazoline Ligands
Marco Durini,[a,b] Eleonora Russotto,[a] Luca Pignataro,[c] Oliver Reiser,*[b] and
Umberto Piarulli*[a]
Dedicated to Professor Cesare Gennari on the occasion of his 60th birthday
Keywords: Supramolecular chemistry / Self-assembly / N ligands / Asymmetric catalysis / Acylation
A new class of oxazoline ligands, named SupraBox, was
studied. These ligands possess an additional urea function-
ality to generate supramolecular bidentate ligands in transi-
tion-metal complexes, by the establishment of hydrogen
bonds between the urea N-hydrogens of one ligand and the
carbonyl oxygen of a second one. A library of 16 SupraBox
formation of copper(II) and palladium(II) complexes was in-
vestigated by MS, UV/Vis and 1H-NMR spectroscopy. The
SupraBox library was screened in the copper-catalyzed
asymmetric benzoylation of vic-diols. Good selectivities were
obtained in the kinetic resolution of racemic hydrobenzoin
[up to 86%ee and selectivity (s) = 28] and in the desym-
ligands was prepared using 5 differently substituted oxazol- metrization of meso-hydrobenzoin (up to 88%ee).
ine nuclei, 4 linkers and 3 different urea substituents. The
with a better capability of controlling a subsequent metal-
Introduction
catalyzed reaction.
The supramolecular assembly of biologically active spe-
Among the different kinds of non-covalent interactions
cies through hydrogen bonding is a widely occurring phe-
that have been used to date for developing supramolecular
nomenon in nature, as exemplified by DNA base pairing,
ligands, hydrogen bonds are arguably the most practical
the secondary or tertiary structure of proteins, or the
and efficient for several reasons: (i) functional groups cap-
mechanism of action of many enzymes. Taking inspiration
able of hydrogen bonding (e.g., amides, ureas, guanidines)
from nature, chemists have designed and realized supra-
are stable and relatively easy to introduce; (ii) hydrogen
molecular catalysts in which a receptor or a cavitand is con-
bonds are created dynamically and reversibly in the reaction
nected to an active site.[1] In a closely related approach, chi-
medium (where catalysis is to take place), are able to self-
ral ligands for transition metals have also been developed
repair when broken, and often coexist with other interac-
that possess, as well as centers for coordinating to a metal
tions in a “non-invasive” manner. In the last few years, sev-
ion, an additional functionality that is capable of ligand–
eral powerful supramolecular bidentate ligands with out-
ligand bonding by non-covalent interactions, such as hydro-
standing reactivity and selectivity have been described, but
gen bonding or coordinative bonding. These ligands are
unfortunately, this concept has so far been exclusively con-
usually referred to as “supramolecular bidentate ligands”.[2]
fined to the use of phosphorus ligands.[2]
This approach reduces the number of degrees of freedom in
In this paper, we report the first example of hydrogen-
the resulting metal coordination complexes compared to
bond-induced assembly of monodentate oxazolines for the
the analogous complexes based on monodentate ligands,
formation of supramolecular bis(oxazoline) metal com-
and this is expected to give a more pre-organized system
plexes and the use of their copper(II) complexes in asym-
metric catalytic transformations.[3]
[a] Università degli Studi dell’Insubria,
Dipartimento di Scienza e Alta Tecnologia,
Via Valleggio 11, 22100 Como, Italy
Fax: +39-031-238-6449
Results and Discussion
E-mail: Umberto.Piarulli@uninsubria.it
[b] Universität Regensburg, Insitut für Organische Chemie,
Universitätstrasse 31, 93053 Regensburg, Germany
Fax: +49-941-943-4121
Bis(oxazolines) (Box) have developed into one of the
most useful ligand classes for asymmetric catalysis, due to
their ability to coordinate a wide variety of metal ions. The
resulting complexes can be used in a great number of cata-
lytic processes with excellent reactivity and selectivity.[4] The
general structural motif of these ligands can be described
E-mail: Oliver.Reiser@chemie.uni-regensburg.de
[c] Università degli Studi di Milano
Dipartimento di Chimica Organica e Industriale
Via G. Venezian 21, 20133 Milano, Italy
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200516.
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FULL PAPER
as being two oxazoline units connected by one of a wide synthesis of ligands 1–14 (Scheme 1), the amino acid linkers
range of linkers. These linkers tune the separation and the (i.e., 18) reacted with different isocyanates in THF or, where
bite angle of the two oxazolines, and might also introduce the substrate had limited solubility, in 2 n NaOH, to give
additional stereogenic elements (centers or axes) to opti- the corresponding acid ureas (i.e., 19).[6] These were then
mize the enantioselectivity of a given asymmetric reaction. coupled to amino alcohols using HBTU (O-benzotriazole-
In our approach, a covalent linker is replaced by a hydro- N,N,NЈ,NЈ-tetramethyluronium hexafluorophosphate) in
gen-bonding interaction between two urea moieties that are dichloromethane. The ring closure and the formation of ox-
connected to the oxazoline rings by different spacers (Fig- azolines 1–14 was achieved in good yields using DAST (di-
ure 1). The urea functionality has been used before as a ethylaminosulfur trifluoride), which had to be used in ex-
self-complementary recognition motif in the formation of cess (2.2 equiv.), probably because of interference with the
supramolecular bidentate phosphane and phosphite li- urea moiety.
gands.[5]
Figure 1. SupraBox: general structure of the ligands and of the
supramolecular bidentate complex.
Thus, the synthesis of a library of “SupraBox” ligands
(1–16, Figure 2) was planned. Their structure allows a mod-
ular synthetic approach and the introduction of several sites
Scheme 1. Synthesis of the SupraBox ligands. Reagents and condi-
tions: (a) RNCO (1 equiv.), THF or aq. NaOH, 60–70%; (b)
iPr2EtN (2.5 equiv.), HBTU (1.3 equiv.), amino alcohol
(1.2 equiv.), CH2Cl2, 0 °C to r.t., 16 h, 85–99%; (c) DAST
(2.2 equiv.), THF, –78 °C to r.t.; (d) K2CO3, 75–90%.
of diversity for steric and electronic tuning of the ligand
properties: (i) the spacer between the oxazoline and the urea
moiety; (ii) the substituent at the oxazoline stereocenter;
(iii) the substitution pattern on the urea moiety.
For the synthesis of ligands 15 and 16, featuring the as-
partic α-pyrrolidinamide linker, a slightly different protocol
Synthesis of the Ligands
The ligands were prepared following a straightforward was followed (Scheme 2). Starting from l- or d-aspartic
and reliable synthetic protocol involving only one or two acid β-allyl ester 21,[7] the corresponding phenyl urea 22
chromatographic purifications (Schemes 1 and 2). For the was assembled and then treated with pyrrolidine to obtain
Figure 2. The SupraBox ligand library.
2
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SupraBox: Chiral Supramolecular Oxazoline Ligands
lecular composition was assessed by ESI-MS spectroscopy,
which revealed one principal peak at m/z = 613.3, corre-
sponding to a copper(I) atom coordinated to two molecules
of ligand, i.e., [CuL2]+. The reduction of Cu2+ to Cu+ has
been reported to occur when ESI is used as an ionization
source.[9] The presence of two ligands coordinated to Cu2+
was further confirmed by a measurement of the complex
absorbance as a function of the ligand/metal ratio, also
known as Yoe–Jones method[10] (Figure 3). This plot
showed a quasi-linear increase of the complex-absorbance
value up to a combining ratio of 2:1. Addition of further
ligand produced an almost negligible variation in the ab-
sorbance. The deviation from linearity could depend on the
stability of the complex with respect to ligand dissoci-
ation:[11] the more stable the complex, the closer the experi-
mental curve approaches a straight line.
Scheme 2. Synthesis of ligands 15 and 16. Reagents and conditions:
(a) PhNCO (1 equiv.), Et3N (1 equiv.), THF, r.t., 88%; (b) iPr2EtN
(2.5 equiv.), HBTU (1.3 equiv.), pyrrolidine (1.2 equiv.), DMF,
78%; (c) pyrrolidine (1.2 equiv.), Ph3P (0.18 equiv.), [Pd(Ph3P)]
(0.04 equiv.), CH2Cl2, 77%; (d) iPr2EtN (2.5 equiv.), HBTU
(1.3 equiv.), l-valinol (1.2 equiv.), CH2Cl2, 60%; (e) DAST
(2.2 equiv.), THF, –78 °C to r.t.; (f) K2CO3, 58%.
the α-pyrrolidinamide derivative 23. The allyl ester was
cleaved by reaction with [Pd(PPh3)4]/pyrrolidine, and the re-
sulting β-carboxylic acid was transformed into the oxazol-
ine nucleus by reaction with (S)-valinol and then DAST-
mediated ring closure.
Altogether, four different amino-acid spacers (β-alanine,
2-amino-isobutyric acid, m-amino benzoic acid and as-
partic acid α-pyrrolidine-carboxamide) were used to impart
different conformational rigidity to the ligands, and so in-
fluence the formation of intramolecular hydrogen bonds be-
tween the urea moieties. In addition, three different isocy-
anates were included in the screening to vary the hydrogen-
bond-forming properties of the ligands, as well as five
amino alcohols derived from natural α-amino acids to tune
the transfer of the stereochemical information. In this way,
a small collection of 16 ligands was prepared for testing.
Figure 3. Yoe–Jones plot of complex absorbance as a function of
ligand/metal ratio of complex [Cu(9)2Cl2]. Ligand (S)-9 was added
in accurately weighed portions to CuCl2 in CH2Cl2, and UV ab-
sorption spectra were recorded after each addition.
The formation of palladium(II) complexes was also in-
vestigated: palladium chloride was treated with 2 equiv. li-
gand (S)-9 in dichloromethane, and the complex [Pd(S-9)2-
Cl2] was isolated by precipitation from hexanes. Since in
this case the complex is diamagnetic, the supramolecular
bidentate ligand [Pd(S-9)2Cl2] could be studied by 1H NMR
spectroscopy. It is important to note that only one set of
signals could be detected in the NMR spectra at room tem-
perature, and the two coordinated molecules of 9, i.e., the
Complexation Studies
Before screening the library of ligands in catalytic appli- one acting as hydrogen-bond donor and the other as ac-
cations, we set out to investigate the formation of transi- ceptor (Figure 4), could not be distinguished. The hydro-
tion-metal complexes of the SupraBox ligands. The struc- gen-bonding state of the NH protons for both the free li-
tures of complexes of supramolecular bidentate ligands gand and the Pd complex was also studied. In particular,
containing additional functionalities capable of hydrogen- the variation of the chemical shifts of the NH signals upon
bonding interactions have usually been assessed spectro- dilution was considered for both the ligand and the Pd
scopically,[8,5c] by 1H, 13C, and 31P-NMR spectroscopy. complex. At 5 mm, the NH protons of the complex reso-
ESI-MS has also been used, since this ionization methodol- nated at higher chemical shifts than did those of the free
ogy allowed the detection of the ion of the self-assembled ligand (5.74 vs. 5.62 ppm for NHA, and 7.03 vs. 6.80 ppm
complex, as has X-ray structural analysis, which showed the for NHB), and their chemical shifts had a lower concentra-
self-organized complex, held together by non-covalent in- tion dependence over the 5–40 mm range (Δδ = 0.1 vs.
teractions (metal coordination, intermolecular hydrogen 0.27 ppm for NHA, and Δδ = 0.1 vs. 0.32 ppm for NHB, see
bonding, and π-stacking).
the Supporting Information for the values and graphics)
The copper(II) complex of ligand (S)-9 was obtained by than those of the free ligand. The temperature dependence
treating it with CuCl2 in CH2Cl2, followed by recrystalli- of the NH signals was also investigated, but on cooling, the
zation of the crude material from CH2Cl2/n-hexane. Its mo- signals broadened and coalesced, and two signals appeared
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M. Durini, E. Russotto, L. Pignataro, O. Reiser, U. Piarulli
FULL PAPER
at temperatures lower than 268 K, which hampered the
In the catalytic reactions, the complexes were preformed
measurement of the temperature coefficient (Δδ/ΔT) of each by stirring a suspension of CuCl2 in a solution of the ligand
NH proton. These experiments, which are commonly used in CH2Cl2 until all of the highly insoluble copper salt be-
to differentiate between random-coil peptides and peptides came soluble by complexation with the ligand (as seen by
in hydrogen-bonded conformations,[12] indicate that the two the formation of a deeply colored solution). Despite the
ligands coordinated to the metal atom interact intramolecu- structural similarities between 1–16, their performance in
larly by hydrogen bonding.
the asymmetric benzoylation varied considerably, and
rather surprisingly, the best selectivities were obtained with
ligands 9 and 11. Ligands 10 and 12, with benzyl and
phenyl substitution at the stereocenters, substituents that
had proved most successful in the same reaction with bis-
(oxazoline) ligands,[13,14] gave inferior results. From a closer
inspection of the selectivities, the importance of a fine bal-
ance of conformational flexibility, steric hindrance, and
electronic properties becomes evident. In particular, the
meta-disubstituted aromatic linker (Table 1, entries 1–6)
and the Cα-tetrasubstituted amino acid (Aib) hamper
enantioselectivity, probably because of the high degree of
rigidity which does not allow an efficient docking of the
two urea functionalities. In fact, the use of a β-alanine
linker (Table 1, entries 9–14), which is best combined with
an isopropyl or ethyl substitution at the oxazoline moiety,
results in a significant increase in selectivity (Table 1, en-
tries 9 and 11, respectively). Finally, no selectivity was ob-
tained with the monodentate ligand 17, which is not capable
of supramolecular interactions (Table 1, entry 18).
Figure 4. SupraBox: general structure of the ligands and of the
supramolecular bidentate complex.
Enantioselective Catalytic Applications
Copper bis(oxazoline) complexes have been shown to be
efficient catalysts in the kinetic resolution of racemic di-
ols,[13] and in particular of hydrobenzoin, by benzo-
ylation.[14] For this reason, we decided to screen ligands 1–
16 in this reaction (Table 1). In addition, mono(oxazoline)
17[15] (Figure 2) devoid of functional groups capable of
forming hydrogen bonds, was added to the screening to
confirm the importance of the supramolecular interaction.
Asymmetric catalytic acylation with copper(II) com-
plexes has also been applied to the desymmetrization of
meso diols,[17] albeit with ee values lower than those ob-
tained in the kinetic resolution (58%ee in the asymmetric
benzoylation of meso-hydrobenzoin[17a]). We tested a selec-
tion of ligands in the desymmetrization of meso-hydroben-
Table 1. Screening of the SupraBox ligands in the copper-catalyzed
enantioselective benzoylation of hydrobenzoin 23.[a]
Table 2. Screening of the SupraBox ligands in the copper-catalyzed
desymmetrization of meso-hydrobenzoin by benzoylation.[a]
Entry
Ligand
Yield
[%][b]
ee [%][c]
Selectivity
(conf.)[d]
(s)[e]
1
2
3
4
5
6
7
8
(S)-1
(R)-2
17
35
38
39
28
34
44
26
44
43
45
47
45
41
37
35
48
40
12 (R,R)
0
1.3
1.0
2.5
1.4
1.4
1.7
7.4
4.3
27
(S)-3
34 (R,R)
14 (R,R)
14 (S,S)
20 (R,R)
64 (R,R)
56 (S,S)
86 (R,R)
70 (R,R)
86 (S,S)
20 (S,S)
2 (R,R)
44 (R,R)
22 (R,R)
36 (R,R)
Ͼ99 (S,S)
0
(S)-4
Entry
Ligand
Yield
[%][b]
ee [%][c]
(R)-5
(conf)[d]
(S)-6
(S)-7
1
2
3
4
5
6
7
8
(S)-1
(R)-5
68
74
88
99
44
77
92
70
89
68
62
86
73
2 (1R,2S)
7 (1S,2R)
68 (1R,2S)
26 (1S,2R)
88 (1R,2S)
6 (1R,2S)
78 (1S,2R)
24 (1S,2R)
38 (1R,2S)
40 (1R,2S)
20 (1R,2S)
59[f]
(R)-8
9
(S)-9
(S)-7
10
11
12
13
14
15
16
17
18
(S)-10
(R)-11
(R)-12
(S)-13
(S)-14
(S,S)-15
(R,S)-16
(R,R)-PhBox[f]
(S)-17
9.5
28
(R)-8
(S)-9
1.8
1.1
3.4
1.8
2.5
Ͼ645[g]
1.0
(S)-10
(R)-11
(R)-12
9
(S)-14
10
11
12
13
(S,S)-15
(R,S)-16
(R,R)-PhBox[e]
(S)-17
0
[a] Reagents and conditions: CuCl2 (5 mol-%), ligand (10 mol-%),
PhCOCl (0.5 equiv.), iPrEt2N (1 equiv.), CH2Cl2, 3 h, 0 °C. [b] Iso-
lated yield after chromatography. [c] Determined by chiral HPLC.
[d] Determined according to ref.[14] [e] Determined according to
ref.[16] [f] (R,R)-PhBox = 2,2-isopropylidenebis[(4R)-4-phenyl-2-ox-
azoline]. [g] See ref.[14a]
[a] Reagents and conditions: CuCl2 (5 mol-%), ligand (10 mol-%),
PhCOCl (0.5 equiv.), iPrEt2N (1 equiv.), CH2Cl2, 3 h, 0 °C. [b] Iso-
lated yield after chromatography. [c] Determined by chiral HPLC.
[d] Determined according to ref.[17a] [e] (R,R)-PhBox = 2,2-isoprop-
ylidenebis[(4R)-4-phenyl-2-oxazoline]. [f] See ref.[17a]
4
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SupraBox: Chiral Supramolecular Oxazoline Ligands
100.56 MHz with complete proton decoupling. Carbon chemical
shifts are reported in ppm (δ) relative to TMS with the respective
solvent resonance as the internal standard (CDCl3, δ = 77.23 ppm;
[D6]DMSO, δ = 39.51 ppm; CD3OD, δ = 49.05 ppm). Infra-red
spectra were recorded with a standard FTIR spectrometer. Optical
rotation values were measured with an automatic polarimeter with
a 1 dm cell at the sodium D line (λ = 589 nm). HPLC was per-
formed with an instrument equipped with a diode array detector,
using a chiral column. High-resolution mass spectra (HRMS) were
performed with a Fourier Transform Ion Cyclotron Resonance
zoin by benzoylation, and the results are collected in
Table 2.
Once again, satisfactory results were obtained with li-
gands 9 and 11 (Table 2, entries 5 and 7). Notably, the Sup-
raBox ligands outperform the classical methylene-bridged
bis(oxazolines) and aza-bis(oxazolines), probably because
the flexibility of the non-covalent linker allows these meso
substrates to be accommodated in the copper(II) coordina-
tion sphere. In contrast, the rigidity of the classical bis(oxa-
zolines) creates a cavity where the C2-symmetric (d,l)-vic- (FT-ICR) Mass Spectrometer APEX II & Xmass software (Bruker
Daltonics) – 4.7 T Magnet (Magnex) equipped with ESI source,
available at CIGA (Centro Interdipartimentale Grandi Apparecchi-
ature) c/o Università degli Studi di Milano. Low-resolution mass
spectra (MS) were acquired either with a Thermo-Finnigan LCQ
Advantage mass spectrometer (ESI ion source) or with a VG Au-
tospec M246 spectrometer (FAB ion source). Elemental analyses
were performed with a Perkin–Elmer Series II CHNS/O Analyzer
2000.
diols can fit better than the σ-symmetric meso diols. Also
in this case, ligand 17, devoid of functionalities that can
as hydrogen-bond donors, catalyzed the benzoylation in an
unselective way (Table 2, entry 13).
Conclusions
A new class of supramolecular bidentate nitrogen ligands
has been investigated. These ligands feature a chiral oxazol-
ine ring and a urea functionality linked by a spacer. A 16-
membered library was prepared, made up of 5 differently
substituted oxazoline nuclei, 4 linkers, and 3 different urea
substituents. The coordination of these ligands to cop-
per(II) and palladium(II) ions was studied, revealing that:
Materials: Commercially available reagents were used as received.
4-aspartic acid β-allyl ester[7] (21) and (S)-4-isopropyl-2-phenyl-4,5-
dihydrooxazole[15] (17) were prepared according to literature pro-
cedures.
3-(3-Phenylureido)benzoic Acid (19a): Phenylisocyanate (1.59 mL,
14.5 mmol, 1.0 equiv.) and 3-aminobenzoic acid (2.0 g, 14.5 mmol,
1.0 equiv.) were dissolved in THF (80 mL), and the reaction mix-
(i) two ligands coordinate to the metal ions via their oxazol- ture was stirred at room temperature for 3 d. The mixture was
treated with cold Et2O to induce precipitation of the product 19a
(2.34 g, 9.15 mmol, 63%) as a fine white powder. Rf = 0.35
(CH2Cl2/MeOH, 95:5). M.p. 152–153 °C. 1H NMR (400 MHz,
CD3OD, 25 °C): δ = 7.03 (m, 1 H), 7.30 (m, 2 H), 7.37–7.46 (m, 3
H), 7.68 (ddd, J = 7.7, 1.5, 1.1 Hz, 1 H), 7.73 (ddd, J = 8.0, 2.3,
1.1 Hz, 1 H), 8.08 (t, J = 1.7 Hz, 1 H) ppm. 13C NMR (100.6 MHz,
CD3OD, 25 °C): δ = 119.1, 119.9, 122.6, 123.2, 123.5, 128.4, 128.6,
ine nitrogen atoms; (ii) the NHs of the urea moiety are in-
tramolecularly hydrogen-bonded, as indicated by the down-
field values and low concentration dependence of their
chemical shifts. The SupraBox library was screened in the
kinetic resolution of racemic hydrobenzoin and the de-
symmetrization of meso-hydrobenzoin by copper-catalyzed
benzoylation. Good selectivities (s) were obtained in the ki-
netic resolution, while the use of SupraBox ligands proved
particularly beneficial in the desymmetrization of hydro-
benzoin, outperforming classical bis(oxazolines).
131.2, 139.0, 139.5, 151.1, 168.2 ppm. IR: ν = 3354, 2724, 1738,
˜
1680, 1649, 1556, 1310, 1156, 1066 cm–1. C14H12N2O3 (256.26):
calcd. C 65.62, H 4.72, N 10.93; found C 63.38, H 4.44, N 10.81.
3-[3-(2-Nitrophenyl)ureido]benzoic Acid (19b): 2-nitrophenyl isocy-
anate (1.0 g, 6.09 mmol, 1.0 equiv.) and 3-aminobenzoic acid
(0.84 g, 6.09 mmol, 1.0 equiv.) were dissolved in THF (60 mL), and
the reaction mixture was stirred at room temperature for 3 d. The
mixture was treated with cold Et2O to induce precipitation of the
product 19b (1.36 g, 4.50 mmol, 74%) as a fine yellow powder. Rf
= 0.26 (CH2Cl2 /MeOH, 95:5). M.p. 174–175 °C. 1H NMR
(400 MHz, DMSO, 25 °C): δ = 7.22 (ddd, J = 8.4, 7.2, 1.2 Hz, 1
H), 7.42 (t, J = 7.8 Hz, 1 H), 7.59 (dt, J = 7.7, 1.2 Hz, 1 H), 7.66–
7.73 (m, 2 H), 8.09 (dd, J = 8.4, 1.6 Hz, 1 H), 8.15 (t, J = 1.8 Hz,
1 H), 8.29 (dd, J = 8.5, 1.2 Hz, 1 H), 9.61 (s, 1 H), 10.03 (s, 1 H),
12.93 (s, 1 H) ppm. 13C NMR (100.6 MHz, DMSO, 25 °C): δ =
119.7, 122.8, 123.0, 123.7, 125.8, 129.6, 131.9, 135.2, 135.4, 138.3,
Further studies are currently underway to find further
applications for this new class of ligands.
Experimental Section
General Remarks: All reactions were carried out in flame-dried
glassware with magnetic stirring under a nitrogen atmosphere un-
less otherwise stated. Dry solvents (over molecular sieves in bottles
with crown cap) were purchased from Fluka and stored under ni-
trogen. Reactions were monitored by analytical thin-layer
chromatography (TLC) using silica gel 60 F254 pre-coated glass
plates (0.25 mm thickness). Visualization was accomplished by irra-
diation with a UV lamp and/or staining with a potassium perman-
ganate alkaline solution. Flash column chromatography was per-
formed using silica gel 60 Å, particle size 40–64 μm, following the
procedure by Still and co-workers.[18] Proton NMR spectra were
recorded with a spectrometer operating at 400.13 MHz. Proton
chemical shifts are reported in ppm (δ) with the solvent reference
relative to tetramethylsilane (TMS) employed as the internal stan-
dard (CDCl3 δ = 7.26 ppm; [D6]DMSO, δ = 2.50 ppm; CD3OD, δ
= 3.33 ppm). The following abbreviations are used to describe spin
multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet, br = broad signal, dd = doublet of doublets. 13C NMR
spectra were recorded with a 400 MHz spectrometer operating at
140.0, 152.3, 167.6 ppm. IR: ν = 3354, 3281, 2724, 1829, 1739,
˜
1652, 1543, 1310, 1155, 1073, 949 cm–1. C14H11N3O5 (301.25):
calcd. C 55.82, H 3.68, N 13.95; found C 55.54, H 3.34, N 14.30.
2-Methyl-2-(3-phenylureido)propanoic Acid (19c): 2-Aminoisobut-
yric acid (3.0 g, 29 mmol, 1.3 equiv.) was suspended in 2 m NaOH
(10 mL), then phenylisocyanate (2.37 mL, 22 mmol, 1.0 equiv.) was
added, and the mixture reaction was stirred for 60 min at room
temperature. The mixture was filtered and the product was precipi-
tated from solution by the slow addition of 1 m HCl. The white
solid was dissolved in 1 m NaOH (10 mL), and the solution was
washed with CH2Cl2. Addition of 1 m HCl induced the precipi-
tation of product 19c (1.73 g, 7.78 mmol, 35%) as a fine white pow-
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O20516
/KAP1
Date: 09-07-12 15:54:43
Pages: 12
M. Durini, E. Russotto, L. Pignataro, O. Reiser, U. Piarulli
FULL PAPER
der. Rf = 0.37 (CH2Cl2/MeOH, 95:5). M.p. 157–158 °C. H NMR
(400 MHz, CD3OH, 25 °C): δ = 1.53 (s, 6 H), 6.41 (s, 1 H), 6.95
(m, 1 H), 7.24 (m, 2 H), 7.30 (m, 2 H), 8.19 (s, 1 H) ppm. 13C
1
for 60 min and then overnight at room temperature. The solvent
was evaporated under reduced pressure, and the mixture was sepa-
rated by flash chromatography eluting with MeOH (gradient from
NMR (100.6 MHz, CD3OD, 25 °C): δ = 24.6, 55.3, 118.6, 121.9, 2 to 10%) in CH2Cl2 to yield product 20 or 25.
128.3, 139.4, 155.7, 177.3 ppm. IR: ν = 3381, 2724, 1704, 1648,
˜
(S)-N-(1-Hydroxy-3-methylbutan-2-yl)-3-(3-phenylureido)benzamide
(20a): According to the general procedure, product 20a (0.578 g,
1.69 mmol, 96%) was obtained as a white solid, starting from acid
19a (0.500 g, 1.95 mmol) and l-valinol. Rf = 0.38 (CH2Cl2/MeOH,
1544, 1308, 1158, 1069 cm–1. C11H14N2O3 (222.24): calcd. C 59.45,
H 6.35, N 12.60; found C 59.55, H 5.55, N 12.61.
3-(3-Phenylureido)propanoic Acid (19d): Phenylisocyanate (5.0 mL,
44 mmol, 1.0 equiv.) was dissolved in THF (220 mL), and then β-
alanine (3.92 g, 44 mmol, 1.0 equiv.) was added. The reaction mix-
1
95:5). M.p. 167–168 °C. [α]2D0 = –44.37 (c = 0.1, CHCl3). H NMR
(400 MHz, CD3OD, 25 °C): δ = 1.00 (d, J = 6.8 Hz, 3 H), 1.03 (d,
ture was stirred at room temperature for 3 d. The mixture was J = 6.8 Hz, 3 H), 2.00 (m, 1 H), 3.67–3.76 (m, 2 H), 3.91 (m, 1 H),
treated with cold Et2O to induce precipitation of the product. After
filtration, the crude product was purified by flash chromatography
eluting with 3Ǟ10% MeOH in CH2Cl2 to yield product 19d
(8.33 g, 40 mmol, 91%) as a fine white powder. Rf = 0.24 (CH2Cl2/
7.03 (t, J = 7.3 Hz, 1 H), 7.30 (m, 2 H), 7.39 (t, J = 7.9 Hz, 1 H),
7.44 (dd, J = 8.7, 1.2 Hz, 2 H), 7.48 (dt, J = 7.7, 1.3 Hz, 1 H), 7.58
(ddd, J = 8.1, 2.1, 1.0 Hz, 1 H), 7.88 (t, J = 1.8 Hz, 1 H) ppm. 13C
NMR (100.6 MHz, CD3OD, 25 °C): δ = 17.8, 18.7, 28.9, 57.4, 61.7,
MeOH, 95:5). M.p. 160–161 °C. 1H NMR (400 MHz, CD3OD, 117.9, 119.0, 121.2, 121.8, 122.6, 128.4, 128.6, 135.7, 138.9, 139.4,
25 °C): δ = 2.55 (t, J = 6.3 Hz, 2 H), 3.47 (t, J = 6.3 Hz, 2 H), 6.98 153.9, 169.2 ppm. IR: ν = 3266, 3200, 2722, 1656, 1609, 1565, 1501,
˜
(t, J = 6.8 Hz, 1 H), 7.25 (dd, J = 8.4, 7.4 Hz, 2 H), 7.33 (m, 2 H) 1310, 1221, 1167, 1089, 989, 840 cm–1. C19H23N3O3 (341.40): calcd.
ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 34.1, 35.2, 119.0,
C 66.84, H 6.79, N 12.31; found C 66.62, H 7.14, N 12.14.
122.0, 128.4, 139.5, 156.8, 174.3 ppm. IR: ν = 3584, 3329, 2725,
˜
(R)-N-(1-Hydroxybutan-2-yl)-3-(3-phenylureido)benzamide (20b):
According to the general procedure, product 20b (0.565 g,
1.72 mmol, 97%) was obtained as a white solid, starting from acid
19a (0.500 g, 1.95 mmol) and (R)-2-aminobutan-1-ol. Rf = 0.40
(CH2Cl2/MeOH, 95:5). M.p. 146–147 °C. [α]2D0 = +42.58 (c = 0.1,
1694, 1638, 1571, 1108 cm–1. C10H12N2O3 (208.21): calcd. C 57.68,
H 5.81, N 13.45; found C 57.73, H 5.57, N 13.81.
3-[3-(2-Nitrophenyl)ureido]propanoic Acid (19e): 2-Nitro-phenyliso-
cyanate (1.000 g, 6.09 mmol, 1.0 equiv.) was dissolved in THF
(30 mL), and then β-alanine (1.085 g, 12.18 mmol, 2.0 equiv.) was CHCl3). 1H NMR (400 MHz, CD3OD, 25 °C): δ = 1.00 (t, J =
added. The reaction mixture was stirred at room temperature for
3 d. The mixture was treated with cold Et2O to induce precipitation
of the product. After filtration, the crude product was purified by
flash chromatography eluting with 3Ǟ5% MeOH in CH2Cl2 to
yield product 19e (1.077 g, 4.25 mmol, 67%) as a fine yellow pow-
7.5 Hz, 3 H), 1.56 (m, 1 H), 1.76 (m, 1 H), 3.63 (dd, J = 5.6, 0.9 Hz,
2 H), 4.03 (m, 2 H), 7.03 (t, J = 7.3 Hz, 1 H), 7.29 (dd, J = 8.5,
7.5 Hz, 2 H), 7.36 (t, J = 7.8 Hz, 1 H), 7.44 (dd, J = 8.7, 1.2 Hz, 2
H), 7.48 (dt, J = 7.7, 1.3 Hz, 1 H), 7.58 (ddd, J = 7.9, 2.2, 1.1 Hz,
1 H), 7.88 (t, J = 1.8 Hz, 1 H), 8.05 (d, J = 8.3 Hz, 1 H) ppm. 13C
NMR (100.6 MHz, CD3OD, 25 °C): δ = 9.6, 23.66, 53.7, 63.43,
117.9, 119.1, 121.2, 121.9, 122.6, 128.5, 128.7, 135.6, 138.9, 139.4,
1
der. Rf = 0.41 (CH2Cl2/MeOH, 95:5). M.p. 160–161 °C. H NMR
(400 MHz, CDCl3, 25 °C): δ = 2.56 (t, J = 6.6 Hz, 2 H), 3.48 (t, J
= 6.6 Hz, 2 H), 7.13 (ddd, J = 8.5, 7.2, 1.3 Hz, 1 H), 7.61 (ddd, J 153.9, 169.2 ppm. IR: ν = 3383, 2724, 1697, 1648, 1542, 1154,
˜
= 8.6, 7.2, 1.6 Hz, 1 H), 8.12 (dd, J = 8.5, 1.6 Hz, 1 H), 8.35 (dd,
J = 8.6, 1.3 Hz, 1 H) ppm. 13C NMR (100.6 MHz, CD3OD, 25 °C):
δ = 33.8, 35.5, 121.4, 122.1, 125.1, 134.6, 135.7, 137.1, 155.4,
1069 cm–1. C18H21N3O3 (327.38): calcd. C 66.04, H 6.47, N 12.84;
found C 65.93, H 6.70, N 12.58.
(S)-N-(1-Hydroxy-3-phenylpropan-2-yl)-3-(3-phenylureido)benz-
amide (20c): According to the general procedure, product 20c
(0.689 g, 1.77 mmol, 100%) was obtained as a white solid, starting
from acid 19a (0.500 g, 1.95 mmol) and (S)-2-amino-3-phenylpro-
pan-1-ol. Rf = 0.34 (CH2Cl2/MeOH, 95:5). M.p. 157–158 °C. [α]2D0
174.0 ppm. IR: ν = 3583, 3393, 3330, 2753, 2360, 1694, 1611, 1582,
˜
1539, 1342, 1258, 1142, 1085, 798 cm–1. C10H11N3O5 (253.21):
calcd. C 47.43, H 4.38, N 16.59; found C 47.62, H 4.23, N 16.29.
3-(3-Cyclohexylureido)propanoic Acid (19f): Cyclohexylisocyanate
(2.86 mL, 22 mmol, 1.0 equiv.) was dissolved in THF (150 mL),
and then β-alanine (2.00 g, 22.4 mmol, 1.0 equiv.) was added. The
reaction mixture was stirred at room temperature for 3 d. The mix-
ture was treated with cold Et2O to induce precipitation of the prod-
uct. After filtration, the crude product was purified by flash
chromatography eluting with 5Ǟ15% MeOH in CH2Cl2 to yield
product 19f (3.60 g, 16.8 mmol, 76%) as a fine white powder. Rf =
0.23 (CH2Cl2/MeOH, 95:5). M.p. 159–160 °C. 1H NMR (400 MHz,
1
= –50.29 (c = 0.1, CHCl3). H NMR (400 MHz, CD3OD, 25 °C):
δ = 2.87 (dd, J = 13.7, 8.6 Hz, 1 H), 3.03 (dd, J = 13.7, 6.2 Hz, 1
H), 3.66 (d, J = 5.5 Hz, 2 H), 4.34 (m, 1 H), 7.04 (t, J = 7.5 Hz, 1
H), 7.17 (m, 1 H), 7.29 (m, 6 H), 7.37 (m, 2 H), 7.45 (dd, J = 8.6,
1.0 Hz, 2 H), 7.56 (dt, J = 7.0, 2.2 Hz, 1 H), 7.79 (m, 1 H) ppm.
13C NMR (100.6 MHz, CD3OD, 25 °C): δ = 36.6, 53.6, 62.9, 117.8,
119.0, 121.1, 121.8, 122.6, 125.9, 128.0, 128.5, 128.6, 129.0, 134.7,
135.5, 138.5, 139.0, 139.3, 153.9, 168.8 ppm. IR: ν = 3324, 2724,
˜
[D6]DMSO, 25 °C): δ = 0.97–1.16 (m, 3 H), 1.18–1.30 (m, 2 H), 1739, 1648, 1543, 1310, 1265, 1155, 1069, 876, 840 cm–1
.
1.50 (m, 1 H), 1.61 (m, 1 H), 1.70 (m, 1 H), 2.31 (t, J = 6.5 Hz, 2 C23H23N3O3 (389.45): calcd. C 70.93, H 5.95, N 10.79; found C
H), 3.15 (q, J = 6.5 Hz, 2 H), 5.74 (t, J = 5.8 Hz, 1 H), 5.83 (d, J
= 7.9 Hz, 1 H), 12.17 (s, 1 H) ppm. 13C NMR (100.6 MHz, [D6]-
DMSO, 25 °C): δ = 24.9, 25.8, 33.7, 35.5, 35.7, 48.1, 157.7,
70.88, H 6.18, N 7.78.
(S)-N-(1-Hydroxy-3,3-dimethylbutan-2-yl)-3-(3-phenylureido)benz-
amide (20d): According to the general procedure, product 20d
(0.552 g, 1.55 mmol, 88%) was obtained as a white solid, starting
from acid 19a (0.500 g, 1.95 mmol) and (S)-2-amino-3,3-dimeth-
ylbutan-1-ol. Rf = 0.37 (CH2Cl2/MeOH, 95:5). M.p. 97–98 °C.
[α]2D0 = –49.69 (c = 0.1, CHCl3). 1H NMR (400 MHz, CD3OD,
25 °C): δ = 1.02 (s, 9 H), 3.63 (dd, J = 11.4, 8.8 Hz, 1 H), 3.68 (dd,
J = 11.4, 3.5 Hz, 1 H), 4.04 (dd, J = 8.8, 3.5 Hz, 1 H), 7.04 (m, 1
H), 7.30 (m, 1 H), 7.40 (t, J = 7.7 Hz, 1 H), 7.42–7.50 (m, 3 H),
7.59 (ddd, J = 7.9, 2.2, 1.1 Hz, 1 H) 7.87 (t, J = 1.7 Hz, 1 H) ppm.
13C NMR (100.6 MHz, CD3OD, 25 °C): δ = 26.0, 33.9, 54.4, 60.9,
173.9 ppm. IR: ν = 3335, 1699, 1626, 1580, 1535, 1307, 1248, 1222,
˜
1080, 921 cm–1. C10H18N2O3 (214.26): calcd. C 56.06; H 8.47; N
13.07; found C 55.87, H 8.62, N 12.72.
General Procedure for the Synthesis of Products 20a–n, 25a and 25b:
Acid 19 or 24 (1.1 equiv.) and N,N-diisopropylethylamine (3 equiv.)
were dissolved in CH2Cl2 (0.1 m), and the solution was cooled to
0 °C. HBTU (1.3 equiv.) was added, and the solution was stirred
at the same temperature for 30 min. Then the amino alcohol
(1.0 equiv.) was added, and the reaction mixture was stirred at 0 °C
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20516
/KAP1
Date: 09-07-12 15:54:43
Pages: 12
SupraBox: Chiral Supramolecular Oxazoline Ligands
117.9, 119.1, 121.3, 121.8, 122.6, 128.5, 128.7, 136.0, 138.9, 139.2,
1062, 845 cm–1. C15H23N3O3 (293.36): calcd. C 61.41, H 7.90, N
153.9, 169.9 ppm. IR: ν = 3278, 3204, 2727, 1670, 1625, 1589, 1553, 14.32; found C 61.22, H 8.01, N 13.97.
˜
1500, 1310, 1233, 1134, 1088, 1047, 840 cm–1. C20H25N3O3
(355.43): calcd. C 67.58, H 7.09, N 11.82; found C 67.44, H 7.16,
N 12.11.
(S)-N-(1-Hydroxy-3-methylbutan-2-yl)-3-(3-phenylureido)propan-
amide (20i): According to the general procedure, product 20i
(0.569 g, 1.94 mmol, 89 %) was obtained as a white solid solid,
starting from acid 19d (0.500 g, 2.4 mmol) and l-valinol. Rf = 0.22
(CH2Cl2/MeOH, 95:5). M.p. 121–122 °C. [α]2D0 = –31.01 (c = 0.1,
CHCl3). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 0.89 (d, J =
6.8 Hz, 3 H), 0.91 (d, J = 6.8 Hz, 3 H), 1.83 (m, 1 H), 2.57 (m, 2
H), 2.90 (br. s, 1 H), 3.47–3.59 (m, 3 H), 3.67 (dd, J = 11.6, 3.2 Hz,
1 H), 3.75 (m, 1 H), 6.85 (d, J = 8.5 Hz, 1 H), 6.98 (m, 1 H), 7.21
(m, 2 H), 7.28 (m, 1 H), 7.44 (m, 1 H), 7.55 (m, 1 H), 7.86 (br. s,
1 H) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 18.9, 19.4,
29.1, 36.5, 37.2, 57.4, 63.3, 119.8, 123.1, 128.9, 138.7, 156.9,
(R)-N-(2-Hydroxy-1-phenylethyl)-3-(3-phenylureido)benzamide
(20e): According to the general procedure, product 20e (0.420 g,
1.12 mmol, 98%) was obtained as a white solid, starting from acid
19a (0.320 g, 1.25 mmol) and (R)-2-amino-2-phenylethanol. Rf =
0.39 (CH2Cl2/MeOH, 95:5). M.p. 112–113 °C. [α]2D0 = –46.89 (c =
1
0.1, CHCl3). H NMR (400 MHz, CD3OD, 25 °C): δ = 3.87 (d, J
= 6.6 Hz, 2 H), 5.21 (t, J = 6.6 Hz, 1 H), 7.02 (t, J = 7.3 Hz, 1 H),
7.23–7.45 (m, 10 H), 7.51 (d, J = 7.7 Hz, 1 H), 7.58 (dd, J = 8.0,
1.1 Hz, 1 H), 7.90 (s, 1 H) ppm. 13C NMR (100.6 MHz, CD3OD,
25 °C): δ = 56.4, 64.7, 118.0, 119.1, 121.3, 122.0, 122.6, 126.6,
127.0, 128.1, 128.5, 128.7, 135.3, 138.9, 139.4, 139.9, 153.9,
173.4 ppm. IR: ν = 3337, 3243, 3087, 2478, 2419, 1670, 1632, 1560,
˜
1503, 1354, 1295, 1260, 1141, 1117, 1063, 1029, 970, 760 cm–1
.
C15H23N3O3 (293.36): calcd. C 61.41, H 7.90, N 14.32; found C
61.21, H 8.02, N 14.72.
168.9 ppm. IR: ν = 3300, 3205, 2727, 1646, 1621, 1599, 1563, 1348,
˜
1298, 1235, 1175, 1065, 844 cm–1. C22H21N3O3 (375.42): calcd. C
70.38, H 5.64, N 11.19; found C 70.37, H 5.73, N 12.11.
(S)-N-(1-Hydroxy-3-phenylpropan-2-yl)-3-(3-phenylureido)propan-
amide (20j): According to the general procedure, product 20j
(0.802 g, 2.35 mmol, 98%) was obtained as a white solid, starting
from acid 19d (0.500 g, 2.4 mmol) and (S)-2-amino-3-phenylpro-
pan-1-ol. Rf = 0.30 (CH2Cl2/MeOH, 95:5). M.p. 131–132 °C. [α]2D0
(S)-N-(1-Hydroxy-3-methylbutan-2-yl)-3-[3-(2-nitrophenyl)ureido]-
benzamide (20f): According to the general procedure, product 20f
(0.568 g, 1.47 mmol, 97%) was obtained as a yellow solid, starting
from acid 19b (0.500 g, 1.66 mmol) and l-valinol. Rf = 0.36
(CH2Cl2/MeOH, 95:5). M.p. 140–141 °C. [α]2D0 = –47.64 (c = 0.1,
CHCl3). 1H NMR (400 MHz, CD3OD, 25 °C): δ = 1.00 (d, J =
6.8 Hz, 1 H), 1.03 (d, J = 6.8 Hz, 1 H), 2.01 (m, 1 H), 3.71 (m, 2
H), 3.92 (m, 1 H), 7.19 (ddd, J = 8.4, 7.4, 1.3 Hz, 1 H), 7.42 (t, J
= 7.8 Hz, 1 H), 7.51 (dt, J = 7.8, 1.3 Hz, 1 H), 7.67 (m, 2 H), 7.97
(t, J = 1.8 Hz, 1 H), 8.19 (dd, J = 8.4, 1.4 Hz, 1 H), 8.48 (dd, J =
8.6, 1.2 Hz, 1 H) ppm. 13C NMR (100.6 MHz, CD3OD, 25 °C): δ
= 17.8, 18.7, 28.9, 57.4, 61.7, 118.2, 121.6, 122.0, 122.3, 125.2,
1
= –34.68 (c = 0.1, CHCl3). H NMR (400 MHz, CD3OD, 25 °C):
δ = 2.38 (t, J = 6.4 Hz, 2 H), 2.71 (dd, J = 13.8, 8.1 Hz, 1 H), 2.90
(dd, J = 13.8, 6.2 Hz, 1 H), 3.38 (m, 2 H), 3.53 (m, 2 H), 4.12 (m,
1 H), 6.97 (m, 1 H), 7.15 (m, 1 H), 7.21–7.27 (m, 6 H), 7.33 (m, 2
H) ppm. 13C NMR (100.6 MHz, CD3OD, 25 °C): δ = 35.9, 36.1,
36.6, 52.8, 62.9, 118.8, 122.1, 125.9, 126.9, 127.9, 128.4, 128.9,
138.4, 139.5, 156.8, 172.5 ppm. IR: ν = 3320, 2724, 2453, 1829,
˜
1738, 1625, 1545, 1308, 1263, 1156, 1071, 1036 cm–1. C19H23N3O3
(341.40): calcd. C 66.84, H 6.79, N 12.31; found C 67.01, H 6.46,
N 12.37.
128.7, 134.7, 135.2, 135.8, 153.2, 169.2 ppm. IR: ν = 3296, 3205,
˜
1722, 1697, 1628, 1604, 1565, 1340, 1252, 1194, 1141, 1074, 1028,
846 cm–1. C19H22N4O5 (386.41): calcd. C 59.06, H 5.74, N 14.50;
found C 59.27, H 6.09, 14.83.
(R)-N-(1-Hydroxybutan-2-yl)-3-(3-phenylureido)propanamide (20k):
According to the general procedure, product 20k (0.604 g,
2.16 mmol, 99%) was obtained as a white solid, starting from acid
19d (0.500 g, 2.4 mmol) and (R)-2-aminobutan-1-ol. Rf = 0.23
(CH2Cl2/MeOH, 94:6). M.p. 131–132 °C. [α]2D0 = +32.01(c = 0.1,
CHCl3). 1H NMR (400 MHz, CD3OD, 25 °C): δ = 0.93 (t, J =
7.4 Hz, 3 H), 1.42 (m, 1 H), 1.63 (m, 1 H), 2.46 (m, 2 H), 3.43–
3.52 (m, 4 H), 3.80 (m, 1 H), 6.97 (m, 1 H), 7.23 (m, 2 H), 7.33
(m, 2 H) ppm. 13C NMR (100.6 MHz, CD3OD, 25 °C): δ = 18.6,
23.9, 36.5, 37.3, 53.9, 64.8, 119.8, 123.0, 128.9, 138.9, 157.0,
(S)-N-(1-Hydroxy-3-methylbutan-2-yl)-2-methyl-2-(3-phenylureido)-
propanamide (20g): According to the general procedure, product
20g (0.630 g, 2.04 mmol, 100%) was obtained as a white solid,
starting from acid 19c (0.500 g, 2.25 mmol) and l-valinol. Rf = 0.25
(CH2Cl2/MeOH, 95:5). M.p. 135–136 °C. [α]2D0 = –38.27 (c = 0.1,
CHCl3). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 0.86 (d, J =
6.8 Hz, 3 H), 0.89 (d, J = 6.7 Hz, 3 H), 1.52 (s, 3 H), 1.53 (s, 3 H),
1.70 (m, 1 H), 3.39 (t, J = 10.2 Hz, 1 H), 3.70 (m, 2 H), 3.98 (br.
s, 1 H), 6.43 (s, 1 H), 6.86 (d, J = 9.8 Hz, 1 H), 6.94 (t, J = 7.2 Hz,
1 H), 7.15 (t, J = 7.6 Hz, 2 H), 7.28 (d, J = 7.7 Hz, 2 H), 8.09 (s,
1 H) ppm. 13C NMR (100.6 MHz, CHCl3, 25 °C): δ = 19.2, 19.7,
24.7, 26.9 29.1, 56.8, 57.9, 64.2, 120.1, 123.0, 128.7, 138.7, 156.1,
173.3 ppm. IR: ν = 3327, 3265, 2724, 1738, 1647, 1557, 1307, 1154,
˜
1070 cm–1. C14H21N3O3 (279.33): calcd. C 60.20, H 7.58, N 15.04;
found C 60.42, H 7.59, N 14.79.
(R)-N-(2-Hydroxy-1-phenylethyl)-3-(3-phenylureido)propanamide
(20l): According to the general procedure, product 20l (0.505 g,
1.54 mmol, 64%) was obtained as a white solid, starting from acid
19d (0.500 g, 2.4 mmol) and (R)-2-amino-2-phenylethanol. Rf =
0.31 (CH2Cl2/MeOH, 95:5). M.p. 119–120 °C. [α]2D0 = –37.23 (c =
177.4 ppm. IR: ν = 3358, 2724, 1649, 1578, 1542, 1310, 1150, 1133,
˜
1087, 965 cm–1. C16H25N3O3 (307.39): calcd. C 62.52, H 8.20, N
13.67; found C 62.22, H 8.06, N 14.01.
(R)-N-(1-Hydroxybutan-2-yl)-2-methyl-2-(3-phenylureido)propan-
amide (20h): According to the general procedure, product 20h
(0.630 g, 2.04 mmol, 100%) was obtained as a white solid, starting
from acid 19c (0.500 g, 2.25 mmol) and (R)-2-aminobutan-1-ol. Rf
= 0.27 (CH2Cl2/MeOH, 95:5). M.p. 137–138 °C. [α]2D0 = +39.99 (c
1
0.1, CHCl3). H NMR (400 MHz, CD3OD, 25 °C): δ = 2.53 (m, 2
H), 3.47 (t, J = 6.5 Hz, 2 H), 3.77 (dd, J = 11.2, 7.7 Hz, 1 H), 3.75
(dd, J = 11.2, 5.3 Hz, 1 H), 5.01 (dd, J = 7.7, 5.3 Hz, 1 H), 6.97
(tt, J = 7.3, 1.2 Hz, 1 H), 7.20–7.35 (m, 9 H) ppm. 13C NMR
(100.6 MHz, CD3OD, 25 °C): δ = 35.9, 36.0 55.6, 64.9, 118.8,
122.0, 126.6, 127.0, 128.1, 128.4, 139.5, 139.9, 156.8, 172.5 ppm.
1
= 0.1, CHCl3). H NMR (400 MHz, CD3OD, 25 °C): δ = 0.94 (t,
J = 7.6 Hz, 3 H), 1.46 (m, 1 H), 1.50 (s, 6 H), 1.62 (m, 1 H), 3.52
(d, J = 5.4 Hz, 2 H), 3.81 (m, 1 H), 6.97 (t, J = 7.3 Hz, 1 H), 7.23
(m, 2 H), 7.33 (dd, J = 8.5, 1.0 Hz, 2 H) ppm. 13C NMR
(100.6 MHz, CHCl3, 25 °C): δ = 10.6, 23.4, 24.8, 26.9, 53.9, 56.7,
IR: ν = 3382, 3308, 2462, 2364, 1644, 1598, 1544, 1313, 1243, 1153,
˜
1125, 1078, 1056, 905 cm–1. C18H21N3O3 (327.38): calcd. C 66.04,
H 6.47, N 12.84; found C 65.89, H 6.75, N 12.56.
65.6, 120.0, 123.0, 128.7, 138.7, 156.0, 177.4 ppm. IR: ν = 3382,
3271, 3133, 2724, 1648, 1598, 1542, 1494, 1312, 1253, 1220, 1168,
(S)-N-(1-Hydroxy-3-phenylpropan-2-yl)-3-[3-(2-nitrophenyl)-
ureido]propanamide (20m): According to the general procedure,
˜
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O20516
/KAP1
Date: 09-07-12 15:54:43
Pages: 12
M. Durini, E. Russotto, L. Pignataro, O. Reiser, U. Piarulli
FULL PAPER
product 20m (0.211 g, 0.546 mmol, 46%) was obtained as a yellow
solid, starting from acid 19e (0.300 g, 1.18 mmol) and (S)-2-amino-
3-phenylpropan-1-ol. Rf = 0.31 (CH2Cl2/MeOH, 95:5). M.p. 146–
147 °C. [α]2D0 = –43.40 (c = 0.1, CHCl3). 1H NMR (400 MHz,
H), 7.68 (ddd, J = 8.1, 2.3, 1.0 Hz, 1 H), 7.96 (t, J = 2.0 Hz, 1 H)
ppm. 13C NMR (100.6 MHz, CD3OD, 25 °C): δ = 8.52, 28.0, 67.1,
72.0, 118.4, 119.0, 122.1, 122.6, 127.8, 128.5, 128.7, 138.9, 139.6,
153.8, 164.6 ppm. IR: ν = 3309, 3281, 1644, 1612, 1592, 1572, 1448,
˜
CD3OD, 25 °C): δ = 2.40 (t, J = 6.6 Hz, 2 H), 2.72 (dd, J = 13.7, 1311, 1298, 1237, 1168, 1080, 1059, 973, 926 cm–1. C18H19N3O2
8.3 Hz, 1 H), 2.90 (dd, J = 13.7, 6.1 Hz, 1 H), 3.41 (m, 2 H), 3.51 (309.36): calcd. C 69.98, H 6.19, N 13.58; found C 70.01, H 6.15,
(dd, J = 11.1, 5.6 Hz, 1 H), 3.56 (dd, J = 10.6, 5.1 Hz, 1 H), 4.14
(m, 1 H), 7.13 (m, 2 H), 7.23 (m, 4 H), 7.61 (ddd, J = 8.7, 7.2,
1.6 Hz, 1 H), 8.13 (dd, J = 8.4, 1.6 Hz, 1 H), 8.35 (dd, J = 8.6,
1.2 Hz, 1 H) ppm. 13C NMR (100.6 MHz, CD3OD, 25 °C): δ =
35.9, 36.2, 36.6, 52.8, 62.8, 121.4, 122.1, 125.1, 125.9, 127.8, 128.9,
N 13.54.
(S)-1-[3-(4-Benzyl-4,5-dihydrooxazol-2-yl)phenyl]-3-phenylurea (3):
According to the general procedure, product 3 (0.518 g, 1.39 mmol,
78%) was obtained as a white solid starting from precursor 20c
(0.693 g, 1.78 mmol). Rf = 0.52 (CH2Cl2/MeOH, 95:5). M.p. 106–
107 °C. [α]2D0 = –37.89 (c = 0.1, CHCl3). 1H NMR (400 MHz,
CHCl3, 25 °C): δ = 2.64 (dd, J = 13.7, 9.0 Hz, 1 H), 3.12 (dd, J =
13.7, 5.1 Hz, 1 H), 4.02 (t, J = 7.8 Hz, 1 H), 4.22 (t, J = 8.8 Hz, 1
H), 4.47 (m, 1 H), 6.95 (t, J = 7.1 Hz, 1 H), 7.11–7.27 (m, 11 H),
134.6, 135.7, 137.1, 138.4, 155.4, 172.2 ppm. IR: ν = 3371, 3329,
˜
3282, 2368, 1676, 1649, 1585, 1556, 1155, 1116, 1082, 960,
840 cm–1. C19H22N4O5 (386.41): calcd. C 59.06, H 5.74, N 14.50;
found C 59.23, H 6.00, 14.76.
(S)-3-(3-Cyclohexylureido)-N-(1-hydroxy-3-methylbutan-2-yl)- 7.54 (d, J = 7.1 Hz, 1 H), 7.94 (d, J = 8.1 Hz, 2 H), 8.04 (s, 1 H)
propanamide (20n): According to the general procedure, product
ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 41.8, 67.6, 72.0,
20n (0.688 g, 2.19 mmol, 99%) was obtained as a white solid, start- 119.8, 120.5, 123.0, 123.1, 123.6, 126.6, 128.1, 128.6, 128.9, 129.0,
ing from acid 19f (0.500 g, 2.3 mmol) and l-valinol. Rf = 0.44
129.1, 137.8, 138.2, 138.7, 154.0, 164.4 ppm. IR: ν = 3353, 2724,
2360, 1649, 1597, 1555, 1310, 1264, 1201, 1154, 1074, 896,
˜
(CH2Cl2/MeOH, 95:5). M.p. 140–141 °C. [α]2D0 = –30.12 (c = 0.1,
CHCl3). 1H NMR (400 MHz, CD3OD, 25 °C): δ = 0.91 (d, J = 845 cm–1. C23H21N3O2 (371.43): calcd. C 74.37, H 5.70, N 11.31;
6.7 Hz, 3 H), 0.94 (d, J = 6.7 Hz, 3 H), 1.17 (m, 3 H), 1.34 (m, 3 found C 77.37, H 5.68, N 10.95.
H), 1.60 (dt, J = 12.6, 3.8 Hz, 1 H), 1.72 (dt, J = 13.3, 3.8 Hz, 1
(S)-1-[3-(4-tert-Butyl-4,5-dihydrooxazol-2-yl)phenyl]-3-phenylurea
H), 1.85 (m, 3 H), 2.42 (m, 2 H), 3.39 (m, 2 H), 3.53 (dd, J = 11.4,
(4): According to the general procedure, product 4 (0.436 g,
6.6 Hz, 1 H), 3.61 (dd, J = 11.3, 4.4 Hz, 1 H), 3.71 (m, 1 H) ppm.
1.29 mmol, 83%) was obtained as a white solid starting from pre-
13C NMR (100.6 MHz, CD3OD, 25 °C): δ = 17.4, 18.6, 24.6, 25.3,
cursor 20d (0.552 g, 1.55 mmol). Rf = 0.48 (CH2Cl2/MeOH, 95:5).
28.6, 33.3, 36.1, 36.5, 56.6, 61.9, 158.9, 172.9 ppm. IR: ν = 3312,
˜
M.p. 170–171 °C. [α]2D0 = –47.13 (c = 0.1, CHCl3). 1H NMR
(400 MHz, CD3OD, 25 °C): δ = 1.02 (s, 9 H), 3.63 (dd, J = 11.5,
8.9 Hz, 1 H), 3.88 (dd, J = 11.5, 3.4 Hz, 1 H), 4.04 (dd, J = 8.9,
3.4 Hz, 1 H), 7.03 (t, J = 7.4 Hz, 1 H), 7.30 (dd, J = 8.4, 7.4 Hz, 2
H), 7.40 (t, J = 7.7 Hz, 1 H), 7.44 (m, 2 H), 7.48 (ddd, J = 7.7, 1.7,
1.1 Hz, 1 H), 7.59 (ddd, J = 8.2, 2.2, 1.1 Hz, 1 H), 7.82 (t, J =
1.7 Hz, 1 H) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 25.8,
33.9, 68.8, 75.9, 119.8, 120.6, 123.0, 123.1, 123.6, 128.3, 129.0,
3278, 2409, 1623, 1578, 1545, 1345, 1214, 1123, 1076, 965 cm–1.
C15H29N3O3 (299.41): calcd. C 60.17; H 9.76; N 14.03; found C
59.89, H 10.09, 14.33.
General Procedure for the Synthesis of Products 1–16: Peptide 20
(1.0 equiv.) was dissolved in THF (0.1 m solution) and cooled to
–78 °C; then DAST (2.2 equiv.) was added dropwise, and the reac-
tion mixture was stirred at the same temperature for 90 min. The
mixture was filtered, and the solvent was evaporated under reduced
pressure. The product was purified by flash chromatography eluting
with MeOH (gradient from 1 to 5%) in CH2Cl2.
138.1, 138.6, 154.0, 163.7 ppm. IR: ν = 3352, 2724, 2360, 1740,
˜
1647, 1596, 1560, 1309, 1264, 1204, 1154, 1073, 897, 799 cm–1
.
C20H23N3O2 (337.42): calcd. C 71.19, H 6.87, N 12.45; found C
71.44, H 7.10, N 12.47.
(S)-1-[3-(4-Isopropyl-4,5-dihydrooxazol-2-yl)phenyl]-3-phenylurea
(1): According to the general procedure, product 1 (0.458 g,
1.42 mmol, 91%) was obtained as a white solid starting from pre-
cursor 20a (0.530 g, 1.55 mmol). Rf = 0.49 (CH2Cl2/MeOH, 95:5).
M.p. 138–139 °C. [α]2D0 = –35.05 (c = 0.1, CHCl3). 1H NMR
(400 MHz, CD2Cl2, 25 °C): δ = 0.92 (d, J = 6.8 Hz, 3 H), 1.01 (d,
J = 6.7 Hz, 3 H), 1.84 (m, 1 H), 4.09 (ddd, J = 9.5, 8.2, 6.4 Hz, 1
H), 4.16 (t, J = 8.2 Hz, 1 H), 4.43 (dd, J = 9.5, 8.3 Hz, 1 H), 7.10
(m, 1 H), 7.14 (br. s, 1 H), 7.25 (br. s, 1 H), 7.28–7.37 (m, 5 H),
7.50 (ddd, J = 8.0, 2.1, 0.9 Hz, 1 H), 7.60 (dt, J = 7.7, 1.1 Hz, 1
H), 7.95 (t, J = 1.7 Hz, 1 H) ppm. 13C NMR (100.6 MHz, CDCl3,
25 °C): δ = 17.6, 18.8, 32.4, 70.6, 71.2, 119.4, 120.8, 123.2, 123.6,
123.9, 128.9, 129.1, 129.3, 138.0, 138.8, 139.0, 153.6, 165.0 ppm.
(R)-1-Phenyl-3-[3-(4-phenyl-4,5-dihydrooxazol-2-yl)phenyl]urea (5):
According to the general procedure, product 5 (0.103 g, 0.29 mmol,
30%) was obtained as a white solid starting from precursor 20e
(0.400 g, 1.06 mmol). Rf = 0.45 (CH2Cl2/MeOH, 95:5). M.p. 134–
135 °C. [α]2D0 = –51.78 (c = 0.1, CHCl3). 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 4.25 (t, J = 8.3 Hz, 1 H), 4.90 (dd, J = 10.1,
8.3 Hz, 1 H), 5.45 (dd, J = 10.1, 8.3 Hz, 1 H), 6.98 (t, J = 7.3 Hz,
1 H), 7.24–7.31 (m, 3 H), 7.34–7.41 (m, 5 H), 7.55 (dd, J = 8.7,
1.1 Hz, 2 H), 7.65 (dt, J = 7.7, 1.3 Hz, 1 H), 7.73 (ddd, J = 8.2,
2.3, 1.1 Hz, 1 H), 8.23 (t, J = 1.9 Hz, 1 H), 8.36 (s, 1 H), 8.52 (s, 1
H) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 69.5, 74.9,
118.2, 118.5, 118.6, 121.5, 121.6, 121.9, 122.1, 126.7, 127.3, 128.1,
IR: ν = 3319, 2725, 1743, 1646, 1595, 1567, 1309, 1262, 1155, 1069, 128.5, 128.7, 128.9, 139.9, 140.4, 142.9, 152.5, 164.3 ppm. IR: ν =
˜
˜
3321, 3278, 2725, 1709, 1656, 1611, 1561, 1311, 1223, 1189, 1063,
970, 840 cm–1. C22H19N3O2 (357.41): calcd. C 73.93, H 5.36, N
11.76; found C 73.57, H 5.63, N 11.46.
801 cm–1. C19H21N3O2 (323.39): calcd. C 70.57, H 6.55, N 12.99;
found C 70.19, H 6.41, N 12.83.
(R)-1-[3-(4-Ethyl-4,5-dihydrooxazol-2-yl)phenyl]-3-phenylurea (2):
According to the general procedure, product 2 (0.370 g, 1.20 mmol,
78%) was obtained as a white solid starting from precursor 20b
(S)-1-[3-(4-Isopropyl-4,5-dihydrooxazol-2-yl)phenyl]-3-(2-nitro-
phenyl)urea (6): According to the general procedure, product 6
(0.500 g, 1.53 mmol). Rf = 0.46 (CH2Cl2/MeOH, 95:5). M.p. 147– (0.441 g, 1.20 mmol, 82%) was obtained as a yellow solid starting
148 °C. [α]2D0 = +43.30 (c = 0.1, CHCl3). 1H NMR (400 MHz,
CD3OD, 25 °C): δ = 0.99 (t, J = 7.3 Hz, 3 H), 1.63 (m, 1 H), 1.74
from precursor 20f (0.565 g, 1.46 mmol). Rf = 0.38 (CH2Cl2/
MeOH, 95:5). M.p. 166–167 °C. [α]2D0 = –49.37 (c = 0.1, CHCl3).
(m, 1 H), 4.14 (t, J = 7.7 Hz, 1 H), 4.24 (m, 1 H), 4.54 (dd, J = 1H NMR (400 MHz, CD2Cl2, 25 °C): δ = (d, J = 6.7 Hz, 3 H), 1.05
9.4, 8.2 Hz, 1 H), 7.02 (m, 1 H), 7.29 (m, 2 H), 7.37 (t, J = 8.2 Hz,
(d, J = 6.7 Hz, 3 H), 1.84 (m, 1 H), 4.07–4.18 (m, 2 H), 4.45 (dd,
1 H), 7.43 (dd, J = 8.7, 1.1 Hz, 2 H), 7.58 (dt, J = 7.7, 1.3 Hz, 1 J = 9.2, 7.8 Hz, 1 H), 7.10 (br. s, 1 H), 7.15 (ddd, J = 8.4, 7.2,
8
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20516
/KAP1
Date: 09-07-12 15:54:43
Pages: 12
SupraBox: Chiral Supramolecular Oxazoline Ligands
1.3 Hz, 1 H), 7.43 (t, J = 7.7 Hz, 1 H), 7.64 (ddd, J = 7.9, 2.1, (m, 1 H), 6.06 (br. s, 1 H), 7.03 (t, J = 7.3 Hz, 1 H), 7.13 (m, 2 H),
1.0 Hz, 1 H), 7.68 (ddd, J = 8.7, 7.1, 1.6 Hz, 1 H), 7.72 (dt, J =
7.16–7.40 (m, 8 H), 7.63 (br. s, 1 H) ppm. 13C NMR (100.6 MHz,
7.7, 1.2 Hz, 1 H), 8.04 (t, J = 2.0 Hz, 1 H), 8.22 (dd, J = 8.6, CDCl3, 25 °C): δ = 28.8, 36.6, 41.6, 66.7, 71.9, 120.5, 123.3, 126.6,
1.6 Hz, 1 H), 8.68 (dd, J = 8.7, 1.1 Hz, 1 H), 9.94 (br. s, 1 H) ppm.
13C NMR (100.6 MHz, CH2Cl2, 25 °C): δ = 17.8, 18.6, 32.8, 70.3,
72.5, 119.7, 121.9, 122.1, 122.9, 123.4, 125.5, 128.8, 129.1, 135.4,
128.6, 129.1, 129.2, 137.7, 139.0, 156.2, 167.4 ppm. IR: ν = 3331,
˜
2724, 1679, 1632, 1595, 1565, 1497, 1444, 1349, 1311, 1242, 1191,
1084, 975, 924 cm–1. C19H21N3O2 (323.39): calcd. C 70.57, H 6.55,
N 12.99; found C 70.78, H 6.32, N 13.04.
136.0, 136.7, 138.4, 151.8, 163.1 ppm. IR: ν = 3339, 3281, 2724,
˜
1650, 1591, 1557, 1309, 1278, 1155, 1066, 823 cm–1. C19H20N4O4
(368.39): calcd. C 61.95, H 5.47, N 15.21; found C 61.71, H 5.84,
N 13.47.
(R)-1-[2-(4-Ethyl-4,5-dihydrooxazol-2-yl)ethyl]-3-phenylurea (11):
According to the general procedure, product 11 (0.410 g,
1.57 mmol, 77%) was obtained as a pale yellow solid starting from
(S)-1-[2-(4-Isopropyl-4,5-dihydrooxazol-2-yl)propan-2-yl]-3-phen- precursor 20k (0.570 g, 2.04 mmol). Rf = 0.57 (CH2Cl2/MeOH,
ylurea (7): According to the general procedure, product 7 (0.501 g,
1.73 mmol, 84%) was obtained as a white solid starting from pre-
cursor 20g (0.635 g, 2.06 mmol). Rf = 0.50 (CH2Cl2/MeOH, 95:5).
M.p. 189–190 °C. [α]2D0 = –43.12 (c = 0.1, CHCl3). 1H NMR
95:5). M.p. 68–69 °C. [α]2D0 = +29.07 (c = 0.1, CHCl3). 1H NMR
(400 MHz, CHCl3, 25 °C): δ = 0.91 (t, J = 7.3 Hz, 3 H), 1.56 (m,
1 H), 1.67 (m, 1 H), 2.69 (t, J = 5.6 Hz, 1 H), 3.57 (m, 2 H), 4.06–
4.20 (m, 2 H), 4.63 (t, J = 8.8 Hz, 1 H), 6.38 (br. s, 1 H), 7.02 (t,
(400 MHz, CD3OD, 25 °C): δ = 0.89 (d, J = 6.7 Hz, 3 H), 0.95 (d, J = 7.7 Hz, 1 H), 7.25 (m, 2 H), 7.39 (d, J = 7.3 Hz, 2 H), 7.75 (br.
J = 6.8 Hz, 3 H), 1.56 (s, 3 H), 1.59 (s, 3 H), 1.82 (m, 1 H), 4.00
(ddd, J = 9.8, 7.2, 5.5 Hz, 1 H), 4.12 (dd, J = 8.6, 7.2 Hz, 1 H),
4.32 (dd, J = 9.8, 8.6 Hz, 1 H), 6.96 (m, 1 H), 7.23 (dd, J = 8.6,
s, 1 H) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 9.8, 24.0,
36.5, 37.3, 53.6, 64.6, 119.6, 122.8, 128.9, 139.2, 156.8, 173.0 ppm.
IR: ν = 3321, 2725, 1640, 1556, 1309, 1243, 1156, 1070 cm–1
.
˜
7.5 Hz, 2 H), 7.31 (dd, J = 8.6, 1.2 Hz, 2 H) ppm. 13C NMR C14H19N3O2 (261.32): calcd. C 64.35, H 7.33, N 16.08; found C
(100.6 MHz, CD3OD, 25 °C): δ = 16.4, 17.5, 25.5, 25.7, 31.9, 51.5,
64.44, H 7.43, N 15.41.
70.0, 71.2, 118.6, 121.9, 128.9, 139.4, 155.5, 172.2 ppm. IR: ν =
˜
(R)-1-Phenyl-3-[2-(4-phenyl-4,5-dihydrooxazol-2-yl)ethyl]urea (12):
According to the general procedure, product 12 (0.257 g,
0.83 mmol, 77%) was obtained as a white solid starting from pre-
cursor 20l (0.500 g, 1.54 mmol). Rf = 0.59 (CH2Cl2/MeOH, 95:5).
3338, 2725, 1646, 1600, 1557, 1543, 1310, 1264, 1152, 1071,
800 cm–1. C16H23N3O2 (289.37): calcd. C 66.41, H 8.01, N 14.52;
found C 66.53, H 8.11, 14.77.
(S)-1-[2-(4-Ethyl-4,5-dihydrooxazol-2-yl)propan-2-yl]-3-phenylurea M.p. 122–123 °C. [α]2D0 = +38.08 (c = 0.1, CHCl3). 1H NMR
(8): According to the general procedure, product 8 (0.441 g,
1.60 mmol, 74%) was obtained as a white solid starting from pre-
cursor 20h (0.636 g, 2.17 mmol). Rf = 0.49 (CH2Cl2/MeOH, 95:5).
M.p. 122–123 °C. [α]2D0 = +40.82 (c = 0.1, CHCl3). 1H NMR
(400 MHz, CHCl3, 25 °C): δ = 2.51 (t, J = 5.8 Hz, 2 H), 3.54 (m,
2 H), 4.06 (t, J = 8.3 Hz, 1 H), 4.56 (dd, J = 10.1, 8.6 Hz, 1 H),
5.09 (t, J = 9.2 Hz, 1 H), 6.18 (t, J = 6.0 Hz, 1 H), 6.97 (m, 1 H),
7.13–7.36 (m, 10 H) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C):
(400 MHz, CD3OD, 25 °C): δ = 0.94 (t, J = 7.3 Hz, 3 H), 1.55 (s, δ = 28.9, 36.6, 67.7, 69.4, 120.1, 122.9, 127.8, 128.8, 129.0, 139.1,
3 H), 1.56 (m, 1 H), 1.57 (s, 3 H), 1.66 (m, 1 H), 4.01 (t, J = 7.6 Hz, 141.8, 156.4, 171.8 ppm. IR: ν = 3310, 2726, 1678, 1620, 1567,
˜
1 H), 4.08 (m, 1 H), 4.39 (dd, J = 9.0, 7.8 Hz, 1 H), 6.96 (t, J =
7.3 Hz, 1 H), 7.23 (t, J = 7.9 Hz, 2 H), 7.30 (dd, J = 8.8, 1.2 Hz, 2
H) ppm. 13C NMR (100.6 MHz, CD3OD, 25 °C): δ = 8.3 25.5,
25.6, 27.6, 51.3, 66.8, 72.3, 118.6, 122.0, 128.3, 139.3, 155.4,
1541, 1310, 1245, 1180, 1076, 978, 845 cm–1. C18H19N3O2 (309.36):
calcd. C 69.88, H 6.12, N 13.58; found C 69.58, H 6.34, N 13.89.
(S)-1-[2-(4-Benzyl-4,5-dihydrooxazol-2-yl)ethyl]-3-(2-nitrophenyl)-
urea (13): According to the general procedure, product 13 (0.101 g,
0.274 mmol, 50%) was obtained as a yellow solid starting from
precursor 20m (0.210 g, 0.543 mmol). Rf = 0.34 (CH2Cl2/MeOH,
172.2 ppm. IR: ν = 3321, 2725, 1661, 1641, 1596, 1587, 1500, 1302,
˜
1250, 1218, 1132, 1082, 1068, 979, 955, 924, 843 cm–1. C15H21N3O2
(275.35): calcd. C 65.43, H 7.69, N 15.26; found C 65.57, H 7.66,
N 15.37.
1
95:5). M.p. 154–155 °C. [α]2D0 = –42.12 (c = 0.1, CHCl3). H NMR
(400 MHz, CDCl3, 25 °C): δ = 2.56 (t, J = 5.7 Hz, 2 H), 2.78 (dd,
(S)-1-[2-(4-Isopropyl-4,5-dihydrooxazol-2-yl)ethyl]-3-phenylurea (9): J = 13.7, 7.9 Hz, 1 H), 3.08 (dd, J = 13.7, 5.4 Hz, 1 H), 3.61 (m, 2
According to the general procedure, product 9 (0.519 g, 1.88 mmol,
99%) was obtained as a white solid starting from precursor 20i
H), 4.10 (dd, J = 8.3, 7.4 Hz, 1 H), 4.33 (t, J = 8.9 Hz, 1 H), 4.49
(m, 1 H), 6.17 (br. s, 1 H), 7.04 (m, 1 H), 7.20–7.35 (m, 5 H), 7.58
(0.560 g, 1.91 mmol). Rf = 0.59 (CH2Cl2/MeOH, 95:5). M.p. 81– (ddd, J = 8.7, 7.3, 1.6 Hz, 1 H), 8.16 (dd, J = 8.4, 1.5 Hz, 1 H),
81 °C. [α]2D0 = –29.80 (c = 0.1, CHCl3). 1H NMR (400 MHz,
CD3OD, 25 °C): δ = 0.89 (d, J = 6.8 Hz, 3 H), 0.94 (d, J = 6.7 Hz,
3 H), 1.74 (m, 1 H), 2.52 (m, 2 H), 3.49 (m, 2 H), 3.91 (m, 1 H),
4.07 (t, J = 7.9 Hz, 1 H), 4.31 (dd, J = 9.8, 8.7 Hz, 1 H), 6.97 (m,
1 H), 7.24 (m, 2 H), 7.33 (dd, J = 8.7, 1.2 Hz, 2 H) ppm. 13C NMR
(100.6 MHz, CD3OD, 25 °C): δ = 17.4, 18.6, 28.6, 36.1, 36.2, 56.6,
8.58 (d, J = 8.6 Hz, 1 H), 9.72 (s, 1 H) ppm. 13C NMR (100.6 MHz,
CDCl3, 25 °C): δ = 28.1, 36.6, 41.5, 66.6, 71.9, 121.3, 121.5, 125.7,
126.7, 128.6, 129.3, 134.7, 135.8, 137.0, 137.4, 153.9, 172.2 ppm.
IR: ν = 3353, 2724, 1651, 1613, 1543, 1309, 1264, 1140, 1104,
˜
794 cm–1. C19H20N4O4 (368.38): calcd. C 61.95, H 5.47, N 15.21;
found C 61.66, H 5.78, N 14.99.
61.8, 118.8, 122, 128.4, 139.5, 156.8, 172.8 ppm. IR: ν = 3205, 2728,
˜
(S)-1-Cyclohexyl-3-[2-(4-isopropyl-4,5-dihydrooxazol-2-yl)ethyl]urea
(14): According to the general procedure, product 14 (0.402 g,
1.42 mmol, 62%) was obtained as a white solid starting from pre-
cursor 20n (0.688 g, 2.30 mmol). Rf = 0.54 (CH2Cl2/MeOH, 95:5).
1694, 1639, 1594, 1527, 1380, 1353, 1168, 1077, 1029, 920,
832 cm–1. C15H21N3O2 (273.35): calcd. C 65.43, H 7.69, N 15.26;
found C 65.61, H 7.99, N 14.61.
(S)-1-[2-(4-Benzyl-4,5-dihydrooxazol-2-yl)ethyl]-3-phenylurea (10): M.p. 103–104 °C. [α]2D0 = –39.45 (c = 0.1, CHCl3). 1H NMR
According to the general procedure, product 10 (0.175 g,
0.541 mmol, 53%) was obtained as a pale yellow solid starting from
(400 MHz, CDCl3, 25 °C): δ = 0.90 (d, J = 6.8 Hz, 3 H), 0.98 (d,
J = 6.8 Hz, 3 H), 1.08–1.39 (m, 6 H), 1.59 (dt, J = 12.8, 3.8 Hz, 1
precursor 20j (0.350 g, 1.03 mmol). Rf = 0.51 (CH2Cl2/MeOH, H), 1.71 (m, 2 H), 1.77 (m, 1 H), 1.92 (m, 2 H), 2.50 (m, 2 H), 3.51
1
95:5). M.p. 130–131 °C. [α]2D0 = –44.65 (c = 0.1, CHCl3). H NMR
(400 MHz, CHCl3, 25 °C): δ = 2.44 (t, J = 5.8 Hz, 2 H), 2.64 (dd,
J = 13.7, 7.8 Hz, 1 H), 2.96 (dd, J = 13.7, 5.6 Hz, 1 H), 3.43–3.62
(m, 2 H), 3.98 (t, J = 7.4 Hz, 1 H), 4.20 (t, J = 8.4 Hz, 1 H), 4.29
(m, 2 H), 3.92 (m, 1 H), 4.02 (t, J = 8.1 Hz, 1 H), 4.32 (dd, J =
9.5, 8.5 Hz, 1 H), 4.61 (d, J = 7.5 Hz, 1 H), 5.49 (br. s, 1 H) ppm.
13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 18.1, 18.7, 24.9, 25.6,
28.6, 32.5, 33.9, 36.6, 49.4, 70.3, 71.3, 157.6, 167.4 ppm. IR: ν =
˜
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Job/Unit: O20516
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Date: 09-07-12 15:54:43
Pages: 12
M. Durini, E. Russotto, L. Pignataro, O. Reiser, U. Piarulli
FULL PAPER
3351, 3305, 2350, 1669, 1624, 1579, 1532, 1309, 1251, 1167, 1082,
crude product was purified by flash chromatography eluting with
982, 939, 891, 791 cm–1. C15H27N3O2 (281.39): calcd. C 64.02, H 6% MeOH in CH2Cl2 to yield products 24a,b as yellow solids [(R)-
9.67, N 14.93; found C 63.89, H 9.90, N 14.79.
enantiomer 0.754 g, 2.47 mmol, 77 %. (S)-enantiomer 0.778 g,
2.55 mmol, 80 %]. Rf = 0.30 (CH2Cl2/MeOH, 95:5). M.p. 168–
169 °C. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.85 (m, 2 H),
1.96 (m, 2 H), 2.73 (dd, J = 15.7, 6.2 Hz, 1 H), 2.84, (dd, J = 15.7,
6.1 Hz, 1 H), 3.44 (m, 2 H), 3.62 (m, 1 H), 3.80 (m, 1 H), 5.13 (m,
1 H), 6.75 (d, J = 8.8 Hz, 1 H), 6.97 (t, J = 7.5 Hz, 1 H), 7.21 (t,
J = 7.5 Hz, 2 H), 7.34 (d, J = 7.7 Hz, 2 H), 8.08 (s, 1 H) ppm. 13C
NMR (100.6 MHz, CDCl3, 25 °C): δ = 24.1, 25.9, 37.5, 46.6, 47.1,
4-(Allyloxy)-4-oxo-2-(3-phenylureido)butanoic Acid (22a–b): 4-(All-
yloxy)-2-amino-4-oxobutanoic acid hydrochloride 21a–b (1.20 g,
5.72 mmol, 1.0 equiv.) was suspended in THF (57 mL), and trieth-
ylamine (0.79 mL, 5.72 mmol, 1.0 equiv.) was added dropwise. The
reaction mixture was vigorously stirred for 30 min, then phenyliso-
cyanate (0.65 mL, 5.72 mmol, 1.0 equiv.) was added and the mix-
ture was stirred for 3 d at room temperature. The mixture was
treated with cold Et2O to induce precipitation of a white powder.
The solid was washed with KHSO4 1 m to obtain products 22a and
22b as fine white powders (R-enantiomer: 1.394 g, 4.77 mmol, 83%.
S-enantiomer: 1.407 g, 4.81 mmol, 84 %). Rf = 0.28 (CH2Cl2/
MeOH, 95:5). M.p. 186–187 °C. 1H NMR (400 MHz, CDCl3,
25 °C): δ = 2.86 (br. s, 2 H), 4.54 (br. s, 2 H), 4.78 (br. s, 1 H), 5.19
(d, J = 10.4 Hz, 1 H), 5.26 (d, J = 17.1 Hz, 1 H), 5.84 (m, 1 H),
6.8 (br. s, 1 H), 6.96 (t, J = 6.8 Hz, 1 H), 7.20 (t, J = 7.1 Hz, 2 H),
7.39 (d, J = 7.0 Hz, 2 H), 8.46 (br. s, 1 H), 11.23 (br. s, 1 H) ppm.
13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 36.5, 49.9, 65.6, 118.4,
48.2, 119.5, 122.7, 128.8, 139.1, 155.4, 170.6, 173.7 ppm. IR: ν =
˜
3347, 3202, 3145, 1728, 1685, 1615, 1553, 1518, 1481, 1312, 1203,
1119, 1046, 997 cm–1. C15H19N3O4 (305.33): calcd. C 59.01, H 6.27,
N 13.76; found C 59.34, H 5.99, N 13.44.
(S)-N-[(S)-1-Hydroxy-3-methylbutan-2-yl]-4-oxo-3-(3-phenyl-
ureido)-4-(pyrrolidin-1-yl)butanamide (25a): According to the gene-
ral procedure, product 25a (0.154 g, 0.39 mmol, 60%) was obtained
as a yellow pale oil starting from acid 24a (0.200 g, 0.65 mmol) and
l-valinol. Rf = 0.33 (CH2Cl2/MeOH, 95:5). [α]2D0 = –78.04 (c = 0.1,
CHCl3). 1H NMR (400 MHz, CD3OD, 25 °C): δ = 0.91 (d, J =
6.8 Hz, 3 H), 0.94 (d, J = 6.7 Hz, 3 H), 1.82–1.93 (m, 2 H), 2.00
(m, 1 H), 2.57 (dd, J = 14.4, 7.4 Hz, 1 H), 2.72 (dd, J = 14.4,
6.7 Hz, 1 H), 3.38–3.60 (m, 4 H), 3.69 (m, 2 H), 3.79 (m, 1 H), 5.02
(t, J = 7.2 Hz, 1 H), 6.98 (m, 1 H), 7.24 (m, 2 H), 7.33 (m, 2 H)
ppm. 13C NMR (100.6 MHz, CD3OD, 25 °C): δ = 17.4, 18.6, 23.7,
25.5, 28.5, 38.4, 45.9, 46.5, 48.8, 56.7, 61.7, 118.8, 122.2, 128.4,
119.4, 122.6, 128.8, 131.8, 139.1, 156.5, 170.9 ppm. IR: ν = 3311,
˜
2738, 2603, 2531, 2496, 1716, 1702, 1596, 1547, 1397, 1172, 1072,
1036, 851, 807 cm–1. C14H16N2O5 (292.29): calcd. C 57.53, H 5.52,
N 9.58; found C 57.89, H 5.87, N 9.34.
Allyl 4-Oxo-3-(3-phenylureido)-4-(pyrrolidin-1-yl)butanoate (23a,b):
4-(Allyloxy)-4-oxo-2-(3-phenylureido)butanoic acid 22a,b (1.300 g,
4.45 mmol, 1.0 equiv.) and N,N-diisopropylethylamine (1.90 mL,
11.1 mmol, 2.5 equiv.) were dissolved in DMF (45 mL), and the
solution was cooled to 0 °C. HBTU (1.3 equiv.) was added, and
the solution was stirred at the same temperature for 30 min. Then
pyrrolidine (0.44 mL, 5.34 mmol, 1.2 equiv.) was added, and the
reaction mixture was stirred at 0 °C for 60 min and then overnight
at room temperature. The solvent was evaporated under reduced
pressure, and the mixture was separated by flash chromatography
eluting with MeOH (gradient from 2 to 6%) in CH2Cl2 to yield
products 23a,b as pale yellow oils (R-enantiomer: 1.122 g,
3.24 mmol, 73%. S-enantiomer: 1.199 g, 3.47 mmol, 78%). Rf =
139.2, 155.8, 170.7 ppm. IR: ν = 3310, 3259, 2767, 2456, 2412,
˜
1665, 1565, 1508, 1459, 1334, 1300, 1211, 1098, 980, 876 cm–1
.
C20H30N4O4 (390.48): calcd. C 61.52, H 7.74, N 14.35; found C
61.66, H 7.60, N 14.53.
(R)-N-[(S)-1-Hydroxy-3-methylbutan-2-yl]-4-oxo-3-(3-phenyl-
ureido)-4-(pyrrolidin-1-yl)butanamide (25b): According to the gene-
ral procedure, product 25b (0.144 g, 0.37 mmol, 56%) was obtained
as a yellow pale oil starting from acid 24b (0.200 g, 0.65 mmol) and
l-valinol. Rf = 0.33 (CH2Cl2/MeOH, 95:5). [α]2D0 = –12.35 (c = 0.1,
CHCl3). 1H NMR (400 MHz, CD3OD, 25 °C): δ = 0.89 (d, J =
6.8 Hz, 3 H), 0.93 (d, J = 6.7 Hz, 3 H), 1.80–1.92 (m, 3 H), 2.00
(m, 2 H), 2.58 (dd, J = 14.3, 6.8 Hz, 1 H), 2.73 (dd, J = 14.3,
7.4 Hz, 1 H), 3.35–3.63 (m, 4 H), 3.70 (m, 2 H), 3.82 (m, 1 H), 4.99
(t, J = 7.0 Hz, 1 H), 6.98 (m, 1 H), 7.24 (m, 2 H), 7.33 (dd, J =
8.8, 1.2 Hz, 2 H) ppm. 13C NMR (100.6 MHz, CD3OD, 25 °C): δ
= 17.3, 18.6, 23.7, 25.5, 28.5, 38.3, 45.9, 46.5, 48.7, 56.7, 61.7,
1
0.28 (CH2Cl2/MeOH, 95:5). H NMR (400 MHz, CDCl3, 25 °C):
δ = 1.88 (m, 2 H), 1.99 (m, 2 H), 2.68 (dd, J = 15.8, 6.7 Hz, 1 H),
2.89 (dd, J = 15.8, 7.4 Hz, 1 H), 3.42 (m, 2 H), 3.67 (m, 1 H), 3.78
(m, 1 H), 4.59 (t, J = 1.3 Hz, 1 H), 4.61 (t, J = 1.3 Hz, 1 H), 5.01
(t, J = 7.0 Hz, 1 H), 5.20 (ddd, J = 10.5, 2.7, 1.2 Hz, 1 H), 5.31
(ddd, J = 17.2, 3.0, 1.6 Hz, 1 H), 5.92 (m, 1 H), 6.98 (m, 1 H), 7.24
(m, 2 H), 7.34 (dd, J = 8.8, 1.0 Hz, 2 H) ppm. 13C NMR
(100.6 MHz, CDCl3, 25 °C): δ = 23.7, 25.5, 36.6, 46.0, 46.5, 48.2,
65.1, 117.2, 118.8, 122.3, 128.4, 132.1, 139.2, 155.7, 170.2,
118.7, 122.2, 128.4, 139.2, 155.8, 170.6, 170.8 ppm. IR: ν = 3300,
˜
3256, 2789, 2481, 2426, 1656, 1599, 1548, 1499, 1315, 1224, 1100,
978, 856 cm–1. C20H30N4O4 (390.48): calcd. C 61.52, H 7.74, N
14.35; found C 61.84, H 7.70, N 14.39.
1-[(S)-3-{(S)-4-Isopropyl-4,5-dihydrooxazol-2-yl}-1-oxo-1-(pyrrol-
idin-1-yl)propan-2-yl]-3-phenylurea (15): According to the general
procedure, product 15 (0.083 g, 0.22 mmol, 58%) was obtained as
a yellow solid starting from precursor 25a (0.150 g, 0.38 mmol). Rf
170.4 ppm. IR: ν = 2721, 2656, 2512, 2345, 1721, 1678, 1600, 1329,
˜
1178, 1109, 1074, 997, 856 cm–1. C18H23N3O4 (345.39): calcd. C
62.59, H 6.71, N 12.17; found C 62.33, H 6.57, N 11.99.
4-Oxo-3-(3-phenylureido)-4-(pyrrolidin-1-yl)butanoic Acid (24a,b): = 0.43 (CH2Cl2/MeOH, 95:5). M.p. 122–123 °C. [α]2D0 = –71.70 (c
Allyl 4-oxo-3-(3-phenylureido)-4-(pyrrolidin-1-yl)butanoate 23a,b
1
= 0.1, CHCl3). H NMR (400 MHz, CDCl3, 25 °C): δ = 0.84 (d, J
(1.10 g, 3.18 mmol, 1.0 equiv.) was dissolved in CH2Cl2 (30 mL), = 6.7 Hz, 3 H), 0.92 (d, J = 6.7 Hz, 3 H), 1.66 (m, 1 H), 1.87 (m,
and the solution was cooled to 0 °C. Pyrrolidine (0.31 mL,
3.82 mmol, 1.2 equiv.), triphenylphosphane (0.149 g, 0.57 mmol,
0.18 equiv.) and tetrakis(triphenylphosphane)palladium(0)
(0.147 g, 0.13 mmol, 0.04 equiv.) were added, and the reaction mix-
ture was stirred for 1 h at 0 °C. The mixture was poured into EtOAc
(200 mL) and extracted with satd. NaHCO3 solution (5ϫ 30 mL).
The combined organic layers were acidified to pH 2 with 1 m
KHSO4 solution. The acidified aqueous solution was extracted
with CH2Cl2 (3ϫ 25 mL), and the combined organic layers were
dried with Na2SO4 and concentrated under reduced pressure. The
2 H), 1.96 (m, 2 H), 2.68 (dd, J = 15.2, 6.4 Hz, 1 H), 2.82 (dd, J =
15.2, 8.0 Hz, 1 H), 3.49 (m, 2 H), 3.78–3.92 (m, 4 H), 4.20 (dd, J
= 9.4, 8.2 Hz, 1 H), 5.20 (m, 1 H), 6.88–6.96 (m, 2 H), 7.22 (t, J =
7.6 Hz, 2 H), 7.36 (d, J = 7.6 Hz, 2 H), 8.26 (s, 1 H) ppm. 13C
NMR (100.6 MHz, CDCl3, 25 °C): δ = 18.3, 18.7, 24.3, 25.9, 31.8,
32.6, 46.3, 47.1, 48.3, 70.3, 72.2, 118.8, 122.1, 128.7, 139.6, 155.2,
163.7, 170.9 ppm. IR: ν = 3330, 3223, 2721, 1656, 1623, 1567, 1504,
˜
1398, 1311, 1214, 1200, 1178, 1123, 1083, 1034, 970 cm–1
.
C20H28N4O3 (372.46): calcd. C 64.49, H 7.58, N 15.04; found C
64.67, H 7.30, N 14.99.
10
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20516
/KAP1
Date: 09-07-12 15:54:43
Pages: 12
SupraBox: Chiral Supramolecular Oxazoline Ligands
appan, D. Laventine, O. Reiser, Coord. Chem. Rev. 2008, 252,
702–714; c) G. C. Hargaden, P. J. Guiry, Chem. Rev. 2009, 109,
2505–2550.
1-{(R)-3-[(S)-4-Isopropyl-4,5-dihydrooxazol-2-yl]-1-oxo-1-(pyrrol-
idin-1-yl)propan-2-yl}-3-phenylurea (16): According to the general
procedure, product 16 (0.074 g, 0.20 mmol, 58%) was obtained as
a yellow solid starting from precursor 25b (0.134 g, 0.34 mmol). Rf
= 0.43 (CH2Cl2/MeOH, 95:5). M.p. 126–127 °C. [α]2D0 = –13.76 (c
[5] a) L. K. Knight, Z. Freixa, P. van Leeuwen, J. N. H. Reek, Or-
ganometallics 2006, 25, 954–960; b) A. J. Sandee, A. M.
van der Burg, J. N. H. Reek, Chem. Commun. 2007, 864–866;
c) J. Meeuwissen, M. Kuil, A. M. van der Burg, A. J. Sandee,
J. N. H. Reek, Chem. Eur. J. 2009, 15, 10272–10279.
[6] P. W. Baures, V. B. Oza, S. A. Peterson, J. W. Kelly, Bioorg.
Med. Chem. 1999, 7, 1339–1347.
[7] K. L. Webster, A. B. Maude, M. E. O’Donnell, A. P. Mehrotra,
D. J. Gani, J. Chem. Soc. Perkin Trans. 1 2001, 1673–1695.
[8] a) Y. Liu, C. A. Sandoval, Y. Yamaguchi, X. Zhang, Z. Wang,
K. Kato, K. Ding, J. Am. Chem. Soc. 2006, 128, 14212–14213;
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1
= 0.1, CHCl3). H NMR (400 MHz, CDCl3, 25 °C): δ = 0.83 (d, J
= 6.7 Hz, 3 H), 0.87 (d, J = 6.7 Hz, 3 H), 1.65 (m, 1 H), 1.88 (m,
2 H), 1.97 (m, 2 H), 2.67 (dd, J = 15.6, 6.6 Hz, 1 H), 2.81 (dd, J =
15.6, 8.3 Hz, 1 H), 3.42–3.55 (m, 2 H), 3.83–3.93 (m, 4 H), 4.19
(dd, J = 8.7, 7.9 Hz, 1 H), 5.23 (m, 1 H), 6.89 (d, J = 9.5 Hz, 1 H),
6.94 (t, J = 7.3 Hz, 1 H), 7.21 (t, J = 7.7 Hz, 2 H), 7.35 (d, J =
7.8 Hz, 2 H), 8.35 (s, 1 H) ppm. 13C NMR (100.6 MHz, CDCl3,
25 °C): δ = 18.2, 18.4, 24.3, 25.9, 31.9, 32.4, 46.3, 47.1, 48.0, 70.2,
72.1, 118.8, 122.0, 128.7, 139.8, 155.1, 163.9, 171.0 ppm. IR: ν =
˜
3312, 2729, 1678, 1634, 1603, 1593, 1549, 1334, 1212, 1150, 1115,
1084, 1065, 991, 840 cm–1. C20H28N4O3 (372.46): calcd. C 64.49, H
7.58, N 15.04; found C 64.71, H 7.44, N 14.81.
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Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H NMR and 13C NMR spectra of all important
intermediates and final products.
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for financial support.
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by charge–transfer interactions was recently reported: O. Chu-
zel, C. Magnier-Bouvier, E. Schulz, Tetrahedron: Asymmetry
2008, 19, 1010–1019.
[4] For relevant recent reviews, see: a) G. Desimoni, G. Faita,
K. A. Jørgensen, Chem. Rev. 2006, 106, 3561–3651; b) R. Ras-
Received: April 19, 2012
Published Online: ᭿
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11

Job/Unit: O20516
/KAP1
Date: 09-07-12 15:54:43
Pages: 12
M. Durini, E. Russotto, L. Pignataro, O. Reiser, U. Piarulli
FULL PAPER
Supramolecular Catalysts
SupraBox ligands feature a chiral oxazoline
ring and a urea functionality linked by a
spacer and form supramolecular bidentate
assemblies when coordinated to a metal. A
small SupraBox library was prepared and
tested in the kinetic resolution of racemic
hydrobenzoin and the desymmetrization of
meso-hydrobenzoin by copper-catalyzed
benzoylation.
M. Durini, E. Russotto, L. Pignataro,
O. Reiser,* U. Piarulli* ................... 1–12
SupraBox: Chiral Supramolecular Oxazol-
ine Ligands
Keywords: Supramolecular chemistry / Self-
assembly / N ligands / Asymmetric cataly-
sis / Acylation
12
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0