The facile synthesis of chiral oxazoline catalysts for the diethylzinc addition to aldehydes

Article abstract of DOI:10.1016/j.tetasy.2003.08.029

A range of chiral 4-(1′-hydroxyalkyl)oxazoline catalysts can be obtained in a straightforward two step synthesis, starting from β-hydroxy amino acids like L-serine or L-threonine. Catalyst 4c forms a complex with diethylzinc, effective for the enantioselective addition to aldehydes resulting in high yields and enantiomeric excesses up to >99% even with aliphatic aldehydes. In the latter case the enantiomeric excess showed a marked dependence of the aldehyde's chain length.

Full text of DOI:10.1016/j.tetasy.2003.08.029

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3291–3295
The facile synthesis of chiral oxazoline catalysts for the
diethylzinc addition to aldehydes
Antonio L. Braga,a,* Rodrigo M. Rubim,a Henri S. Schrekker,b Ludger A. Wessjohann,b
Martin W. G. de Bolster,c Gilson Zenia and Jasquer A. Sehnema
aDepartamento de Quimica, Universidade Federal de Santa Maria, 97105-900, Santa Maria, RS, Brazil
bInstitute of Plant Biochemistry, Weinberg 3, D-06120 Halle (Saale), Germany
cFaculty of Sciences Chemistry Division, Department of Organic and Inorganic Chemistry, Vrije Universiteit Amsterdam,
De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands
Received 29 May 2003; accepted 7 August 2003
Abstract—A range of chiral 4-(1%-hydroxyalkyl)oxazoline catalysts can be obtained in a straightforward two step synthesis,
starting from b-hydroxy amino acids like L-serine or L-threonine. Catalyst 4c forms a complex with diethylzinc, effective for the
enantioselective addition to aldehydes resulting in high yields and enantiomeric excesses up to >99% even with aliphatic aldehydes.
In the latter case the enantiomeric excess showed a marked dependence of the aldehyde’s chain length.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
Natural amino acids are readily available from the
chiral pool and are proven to be very attractive for the
synthesis of chiral compounds, including oxazoline cat-
alysts which are easy to synthesize and have been
applied successfully in various asymmetric catalytic
reactions.2 In our ongoing research on amino acid
based chiral catalysts for asymmetric catalysis3 and
screening of biological activity4 we decided to synthe-
size a set of 4-(1%-hydroxyalkyl)oxazolines 4 (Scheme 1)
via a route which could be extended to obtain a focused
library if required.
The synthesis of chiral ligands for the application in
transition metal catalyzed asymmetric reactions is an
area of intensive research.1 The success of a ligand
depends on many factors and is not only based on the
efficiency in the asymmetric catalytic reaction. Other
important factors are: (1) the availability and price of
the starting materials, e.g. from the chiral pool; (2) the
simplicity of the synthesis; (3) the possibility to obtain
structural diversity.
Scheme 1. Synthetic strategy for the synthesis of hydroxymethyl oxazoline ligands, with the combinatorial variables R from three
building blocks/reagents (A–C).
* Corresponding author. Tel.: +11-55-55-220-8761; fax: +11-55-55-220-8031; e-mail: albraga@quimica.ufsm.br
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.08.029

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A. L. Braga et al. / Tetrahedron: Asymmetry 14 (2003) 3291–3295
The hydroxymethyl oxazolines 4a–b, and 6a–c have
already been tested in the diethylzinc addition to ben-
zaldehyde by Williams et al. (Fig. 1).5
4e–f have not been described in the literature previ-
ously.
Our first goal was to test the 4-(1%-hydroxy-
alkyl)oxazolines 4c–f in enantioselective organozinc
additions to aldehydes.9 The diethylzinc addition to
benzaldehyde (Scheme 3) was chosen as the standard
reaction to evaluate the catalyst derivatives.
Figure 1. Hydroxymethyl oxazolines previously applied as
catalysts in the diethylzinc addition.5
Scheme 3. Diethylzinc addition to aromatic aldehydes.
The 2-methyl oxazolines 4a–b were prepared by the
synthetic strategy depicted in Scheme 1 and resulted in
poor enantioselectivities and yields (4b, e.e.=30% (R),
27% yield, 4 h) and lacked stability because they are
prone to hydrolysis. Hydroxymethyl oxazolines 6a–c
With the oxazoline catalysts 4c–f (Table 1) we could
evaluate the influence of the 5-oxazoline subtituent (R1,
in Scheme 1, cf. compounds 4a,b), the 2-oxazoline
substituent (R2) as well as the influence of substituents
near the hydroxyl moiety (R3). We conclude that the
derived
from
(1S,2S)-(+)-2-amino-1-phenyl-1,3-
propanediol 5 proved to be more successful resulting in
an e.e. of 57% (S) and a 65% yield after 18 h for 6b. A
disadvantage of the synthetic strategy used for 6 is the
limitation in being able to vary other substituents than
R2.
absence of the 5-phenyl substituent of 6b5 (A, R1, in
6
Scheme 1) has a dramatic effect on the stereochemical
outcome of the reaction: With 4c the enantiomeric
excess increased to 95% (Table 1, entry 1) after 24 h at
room temperature.
2. Results and discussion
Table 1. The diethylzinc addition to benzaldehyde with
oxazolines 4c–fa
The above results prompted us to synthesize the 2-
phenyl oxazolines 4c–f (Scheme 2) from the natural
amino acid L-serine. An attractive synthetic strategy for
Entry
Cat.
Mol% 4
Yield (%)b
E.e. (%)c,d
4 in which a high structural diversity can be obtained in
a straightforward two step sequence is depicted in
Scheme 1. The commercially available methyl-ester 1 of
1
2
3
4e
5
6
7
4c
4c
4c
4c
4d
4e
4f
10
5
2
10
10
10
10
91
52
41
63
86
85
78
95 (R)
95 (R)
95 (R)
95 (R)
86 (R)
77 (R)
55 (R)
the natural amino acid
L
-serine or optionally
L-
threonine will form the framework (A
6
, R1, in Scheme 1)
of the final hydroxymethyl oxazoline 4. Oxazoline ester
3 can be synthesized by reaction of 1 with a nitrile or
imidate ester hydrochloride 2.6 This transformation,
which offers the possibility to introduce many different
a The reactions were run for 24 h at 20°C, except entry 4.
b Yields are calculated based on GC analysis using naphthalene as the
internal standard.10
substituents in the 2-oxazoline position (B6
, R2, in
Scheme 1) contributes an important part in obtaining
structural diversity. However, most important is the
opportunity to increase the diversity in the sidechain at
position 4 (at C-1%) in the last step. The desired hydroxy-
alkyl oxazolines 4 can be obtained by reduction of 3 or
by reaction with carbon nucleophiles, thus introducing
different substituents at the C4-hydroxymethyl group
c Enantiomeric excesses were determined by chiral GC using
a
hydrodex-b-3P column.
d The absolute configuration was determined by specific rotation and
related to literature data.3a,11
e Reaction at 0°C.
(C
6
, R3, in Scheme 1). Application of existing method-
The first condition tested seemed to be optimal for
catalyst 4c, because variations in catalyst concentration
or a lower temperature decreased the conversion with-
out effecting the enantioselectivity (Table 1, entries
2–4). Under the best reaction conditions for 4c (10
mol%, rt, 24 h) we studied the influence of substituents
ologies or small variations thereof resulted in good
overall yields for 4c (54%),7 4d (31%),8 4e (72%), and 4f
(36%). To the best of our knowledge the oxazolines
at the hydroxymethyl group (C6
, R3, in Scheme 1).
Oxazolines 4d–f with a more crowded sterical environ-
ment around the hydroxyl functionality suffered from a
decrease in the reactivity and enantioselectivity (Table
1, entries 5–7). A Newman-projection can give more
insight into the role of the increased steric bulk around
C-1% (Fig. 2). A comparison of the catalysts 4a–b and
Scheme 2. 2-Phenyl oxazolines. Reagents and conditions: (a)
2, CH2Cl2, NEt3, reflux, 24 h, 90% yield; (b) LiBHEt3, THF,
reflux, 24 h, or (c) R3MgX, THF, reflux, 24 h.
4d/f reveals that the 2-phenyl substituent (B6
, R2, in

A. L. Braga et al. / Tetrahedron: Asymmetry 14 (2003) 3291–3295
3293
Figure 2. Newman projection of catalyst 4.
Scheme 1) is more effective than the 2-methyl
substituent.
Since 4c combined sufficient activity as a catalyst with
good enantioselectivity, its potential in the reaction of
diethylzinc with substituted aromatic aldehydes was
tested (Table 2).
Table 2. The enantioselective addition of diethylzinc to
substituted aromatic aldehydes employing 10 mol% of cat-
alyst 4ca
Entry
Aldehyde
Yield (%)b
E.e. (%)c,d
1
2
3
4
5
6
7
R=H
91
94
65
65
57
75
90
95 (R)
70 (R)
40 (R)
89 (R)
72 (R)
>99 (R)
>99 (R)
R=p-OMe
R=o-OMe
R=p-Me
R=o-Me
R=p-Cl
R=o-Cl
a The reactions were run for 24 h at 20°C.
b Yields are calculated based on GC analysis using naphthalene as the
Figure 3. Transition state models to explain the stereochemi-
cal outcome of the diethylzinc additions to aldehydes.
internal standard.10
c Enantiomeric excesses were determined by chiral GC using
a
hydrodex-b-3P column.
Table 3. The enantioselective addition of diethylzinc to
aliphatic aldehydes employing 10 mol% of catalyst 4ca
d The absolute configuration was determined by specific rotation and
related to literature data.3a,11
Entry
Aldehyde
Yield (%)b
E.e. (%)c,d
A general trend with respect to yield was not observed
when electron donating and withdrawing substituents
were compared. Otherwise, the effect on the enantiose-
lectivity was clear; electron donating substituents led to
a decrease in enantiomeric excess while electron with-
drawing substituents led to an increase. This resulted in
an e.e. value of more than 99% when a chloro sub-
stituent was present (Table 2, entries 6 and 7).
1
2
3
4
5
6
Isobutyraldehyde
Pentanal
Hexanal
Heptanal
Octanal
Decanal
14
35
67
73
65
58
15 (R)
25 (R)
>99 (R)
81 (R)
53 (R)
42 (R)
a The reactions were run for 24 h at 20°C.
b Yields are calculated based on GC analysis using naphthalene as the
internal standard.10
With the less reactive, electron-rich benzaldehydes, the
steric effect obviously also gains some importance. In
this case ortho-substitution resulted in a slight decrease
in yield and enantiomeric excess (Table 2, entry 2
versus 3, and 4 versus 5). The disfavored interaction
between the ortho-substituent and the ethyl groups
attached to the zinc atom no. 2 in the transition state
(Fig. 3) may account for the loss in enantioselectivity.
c Enantiomeric excesses were determined by chiral GC using
a
hydrodex-b-3P column.
d The absolute configuration was determined by specific rotation and
related to literature data.3a,11
four-carbon extension decreased the enantiomeric
excess continuously to 81, 53, and 42% respectively.
This unexpected dependence on the length of the
aliphatic chain was also observed previously with a
disulfide catalyst in our research group,3a,b which
demonstrated once again the difficulty in developing a
catalyst with broad applicability. With some of these
catalysts other chain lengths were prefered. We believe
that the study of the correlation of the chain length and
the enantiomeric excess is mandatory for each ligand
type in order to obtain good results with aliphatic
aldehydes.
The diethylzinc additions to the less reactive and more
often problematic aliphatic aldehydes gave clear results
(Table 3). The tail-length of linear aliphatic aldehydes
had a dramatic effect on the observed enantioselectivity
(Table 3, entries 2–6). Addition of diethylzinc to pen-
tanal gave the secondary alcohol in a low yield and e.e.
(25%). However, the reaction with hexanal resulted in
an excellent e.e. of more than 99%. A one-, two- and

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A. L. Braga et al. / Tetrahedron: Asymmetry 14 (2003) 3291–3295
Interestingly, not only the e.e. values depended on the
chain length; the yields showed an almost identical
relationship. The oxazoline catalytic system seemed to
fail with even the most simplest a-branched aliphatic
aldehyde, isobutyraldehyde, leading to a sluggish reac-
tion and a strongly diminished enantiomeric excess
(Table 3, entry 1). This most likely originates from the
smaller chain length, but additionally may be effected
by the increased bulk.
distilled before use. The diethylzinc was used as pur-
chased. Optical rotations were measured on a Perkin–
Elmer 341 polarimeter. The NMR spectra were
recorded on a Bruker DPX 400 spectrometer using
CDCl3 as the solvent and TMS as the internal stan-
dard. Chemical shifts l are quoted in parts per million
(ppm), and coupling constants J are given in hertz (Hz).
Infrared spectra were recorded in the range of 4000–600
cm−1 using
a Nicolet Magna 550 spectrometer.
Gaschromatography (GC) was performed using a
Varian 3800 gaschromatograph with a hydrodex-b-3P
column. HPLC analyses were carried out on a Shi-
madzu SCL-10 AVP chromatograph using a Diacel
Chiralcel OD-column; solvent: 99:1 hexane:isopro-
panol; flow rate=0.5 ml min−1; UV-detection: 254 nm.
Elemental analysis was performed on a Leco CHNS-
932 analyzer. High resolution mass spectra were
recorded on a Bruker BioApex 70e FT-ICR (Bruker
Daltonics, Billerica, USA) instrument in ESI-mode.
The efficiency of catalyst 4c was diminished in the
reaction of diethylzinc with cinnamaldehyde (Scheme
4).
Scheme 4. Diethylzinc addition to cinnamaldehyde. The
absolute configuration was determined by specific rotation
and related to literature data.11
3.2. Procedure for the preparation of (R)-4-hydroxy-
methyl-2-phenyl-1,3-oxazoline 4c
A solution of LiHBEt3 in THF (1 M, 9 mmol) was
added dropwise to a stirred solution of ester 3 (615 mg,
3.0 mmol) in THF under argon at room temperature.
The mixture was refluxed for 24 h. Subsequently, the
mixture was quenched by the addition of aq. NH4Cl (10
mL). The water layer was extracted with CH2Cl2 (2×10
mL). The collected organic phase was dried over
MgSO4 and concentrated in vacuo to give a crude
colourless oil. Flash chromatography (silica gel, hex-
ane:ethyl acetate=60:40) provided alcohol 4c in 60%
yield. [h]D20=+35 (c 0.42, CH2Cl2). IR (CCl4) (cm−1):
3302 (br); 2934 (w); 1649 (s); 1455 (m). HRMS-ESI m/z
calcd for C10H11O2NNa (M+Na+) 200.0682, found
The stereochemical outcome of these diethylzinc addi-
tions to aldehydes is in agreement with the two possible
anti-transition state structures depicted in Figure 3,
based on the dinuclear zinc complexes proposed by
Noyori et al.10,12 The anti-(R) transition state which
leads to the preferential formation of the (R)-enan-
tiomer appears to be favored because it avoids axial
positioning of the aldehyde alkyl or aryl-group and
thus avoids any destabilizing interactions with the
ethyl-substituent of zinc Zn1 and the oxazoline phenyl.
The syn-transition states with all major substituents
around the Zn2O2 four-membered ring being on the
same side does not appear to be favourable. However,
the unexpected substrate specificity of aliphatic alde-
hydes can not easily be explained by any of these
transition states. Here secondary interactions depending
on the lipophilicity in combination with size seem to
play an important role, and may allow the system to
switch from one preference to another one.
1
200.0683. H NMR (CDCl3, 400 MHz), l: 7.81–7.79
(m, 2H); 7.43–7.26 (m, 3H); 4.44–4.30 (m, 3H); 3.93
(dd, J%=11.6 Hz, J¦=4 Hz, 1H); 3.63 (dd, J%=11.6 Hz,
J¦=4 Hz, 1H); 2.89(s, 1H). 13C NMR (CDCl3, 100
MHz), l: 165.45; 131.38; 128.24; 128.14; 126.95; 69.17;
68.00; 63.60.
3.3. General procedure for the preparation of C-1%-di-
substituted (S)-4-hydroxymethyl-2-phenyl-1,3-oxazolines
4d–f
In conclusion, we have successfully applied a flexible
synthetic strategy for the synthesis of 4-hydroxyalkyl
oxazolines. Application of catalyst 4c in the diethylzinc
addition to aldehydes resulted in clearly improved
enantioselectivities compared to previous results. It can
be shown that there is a distinct substrate specificity for
aliphatic aldehydes. Our results clearly demonstrate the
importance of a versatile synthetic approach like the
one presented here, to allow the individual adaption of
ligands to a desired substrate aldehyde, e.g. by the
construction of focused libraries based on these results.
A solution of RMgX in THF (3 equiv.) was added
dropwise to a stirred solution of ester 3 (615 mg, 3.0
mmol) in THF (5 mL) under argon at room tempera-
ture. The mixture was then refluxed for 24 h. Subse-
quently, the mixture was quenched by the addition of
aq. NH4Cl (15 mL). The water layer was extracted with
CH2Cl2 (3×15 mL). The collected organic phase was
dried over MgSO4 and concentrated in vacuo to give
the crude colourless oil. Flash chromatography (silica
gel, hexane:ethylacetate=64:36) provided alcohol 4d–f
in 54–80% yield.
3. Experimental
3.1. General
3.3.1.
(S)-4-(1%-Methyl-1%-hydroxyethyl)-2-phenyl-1,3-
oxazoline 4d. Yield=54%. [h]2D0=+62 (c 0.73, CH2Cl2).
IR (CCl4) (cm−1): 3196 (br); 2971 (s); 1644 (s); 1450 (m).
HRMS-ESI m/z calcd for C12H15NNaO2 (M+Na+)
All aldehydes used are commercially available and were

A. L. Braga et al. / Tetrahedron: Asymmetry 14 (2003) 3291–3295
3295
228.0995, found 228.0990. Anal. calcd for C12H15NO2:
C, 70.22; H, 7.37; N, 6.82. Found: C, 69.87; H, 7.20; N,
6.53. H NMR (CDCl3, 400 MHz), l: 7.96–7.93 (m,
2H); 7.47–7.26 (m, 3H); 4.42–4.31 (m, 2H); 4.21 (dd,
J%=8 Hz; J¦=2.4 Hz; 1H); 2.42 (s, 1H); 1.31 (s, 3H);
1.17 (s, 3H). 13C NMR (CDCl3, 100 MHz), l: 164.87;
131.40; 128.29; 128.21; 127.44; 75.62; 71.50; 68.75;
26.52; 25.15.
York, 1994; (c) Seyden-Penne, J. Chiral Auxiliaries and
Ligands in Asymmetric Synthesis; Wiley: New York,
1995; (d) Bolm, C.; Hildebrand, J. P.; Mun˜iz, K.; Her-
manns, N. Angew. Chem., Int. Ed. Engl. 2001, 40, 3284–
3308.
1
2. (a) Bolm, C. Angew. Chem., Int. Ed. Engl. 1991, 30,
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345; (c) Togni, A.; Venanzi, L. M. Angew. Chem., Int. Ed.
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P.; Cappiello, J. Tetrahedron: Asymmetry 1998, 9, 1–45;
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Ikeda, I. Synlett 2000, 239–241; (f) Schinnerl, M.; Seitz,
M.; Kaiser, A.; Reiser, O. Org. Lett. 2001, 3, 4259–4262;
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land, N.; Velgaard, T.; Jørgensen, K. A. J. Org. Chem.
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Lin, W.-Q.; Gong, L.-Z.; Mi, A.-Q.; Cui, X.; Jiang,
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3. (a) Braga, A. L.; Appelt, H. R.; Schneider, P. H.; Silveira,
C. C.; Wessjohann, L. A. Tetrahedron: Asymmetry 1999,
10, 1733–1738; (b) Braga, A. L.; Appelt, H. R.;
Schneider, P. H.; Rodrigues, O. E. D.; Silveira, C. C.;
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10413–10416.
3.3.2.
(S)-4-(1%-Ethyl-1%-hydroxypropyl)-2-phenyl-1,3-
oxazoline 4e. Yield=80%. [h]2D0=+41 (c 0.55, CH2Cl2).
IR (CCl4) (cm−1): 3418 (br); 2956 (s); 1645 (s); 1450 (m).
HRMS-ESI m/z calcd for C14H19NNaO2 (M+Na+)
256.1308, found 256.1301. 1H NMR (CDCl3, 400
MHz), l: 7.95–7.93 (m, 2H); 7.47–7.35 (m, 3H); 4.37–
4.28 (m, 3H); 1.78–1.74 (m, 3H); 1.51–1.48 (m, 1H);
1.37–1.36 (m, 1H); 0.94 (t, J=7.6 Hz, 3H); 0.89 (t,
J=7.6 Hz, 3H). 13C NMR (CDCl3, 100 MHz), l:
164.66; 131.25; 128.22; 128.14; 127.60; 75.16; 72.53;
68.14; 28.38; 26.58; 7.71; 7.50.
3.3.3. (S)-4-(Hydroxydiphenylmethyl)-2-phenyl-1,3-oxa-
zoline 4f. Yield=80%. [h]2D0=−41 (c 0.79, CH2Cl2). IR
(CCl4) (cm−1): 3541 (s); 2959 (m); 1644 (s); 1495 (s);
1455 (s); 1355 (s). HRMS-ESI m/z calcd for C22H20O2N
1
(M+H+) 330.1489, found 330.1482. H NMR (CDCl3,
400 MHz), l: 7.92–7.26 (m, 15H); 5.45 (t, J=9.4 Hz,
1H); 4.22 (m, 2H); 2.64 (s, 1H). 13C NMR (CDCl3, 100
MHz), l: 166.58; 145.97; 144.17; 131.57; 128.27; 128.21;
127.90; 127.41; 127.22; 127.12; 127.02; 126.87; 125.76;
78.22; 73.18; 69.24.
4. Rossato, J. I.; Ketzer, L. A.; Centuria˜o, F. B.; Silva, S. J.
N.; Lu¨dtke, D. S.; Zeni, G.; Braga, A. L.; Rubin, M. A.;
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10. Wolf, C.; Francis, C. J.; Hawes, P. A.; Shah, M. Tetra-
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cited therein.
3.4. General procedure for the diethylzinc addition to
aldehydes
In a 25 mL flask, a solution of toluene (7 mL), aldehyde
(1.0 mmol), and catalyst (0.25 mmol) was stirred for 30
min at room temperature. Diethylzinc (1 M in hexane,
2.5 mmol) was slowly injected under constant stirring.
Stirring was continued for 24 h at room temperature.
Cooling (0°C) of the reaction mixture was followed by
the slow addition of HCl solution (aq., 1 M, 5 mL).
The organic layer was separated and washed with HCl
solution (aq., 1 M, 2×8 mL). Drying over sodium
sulfate, filtration, and evaporation of the solvent in
vacuo yielded the crude alcohol, which was analysed by
GC.
11. (a) Cho, B. T.; Chun, Y. S. Tetrtahedron: Asymmetry
1998, 9, 1489–1492; (b) Huang, W.-S.; Hu, Q.-S.; Pu, L.
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information).
Acknowledgements
The authors wish to thank CAPES and DAAD (Ger-
man Academic Exchange Service) for travel grants as
part of PROBRAL, and CNPq, FAPERGS for finan-
cial support.
12. (a) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed.
Engl. 1991, 30, 49–69; (b) Yamakawa, M.; Noyori, R. J.
Am. Chem. Soc. 1995, 117, 6327–6335; (c) Goldfuss, B.;
Houk, K. N. J. Org. Chem. 1998, 63, 8998–9006 and
references cited therein; (d) Va´zquez, J.; Perica`s, M. A.;
Maseras, F.; Lledo´s, A. J. Org. Chem. 2000, 65, 7303–
7309; (e) Jimeno, C.; Pasto´, M.; Riera, A.; Perica`s, M. A.
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