The first use of chiral oxazoline ligands in the highly enantioselective diethylzinc addition to diphenylphosphinoyl imines

Article abstract of DOI:10.1016/S0040-4039(02)00014-X

A series of chiral oxazolines, which had been conveniently prepared from commercially available (1S,2S)-2-amino-1-phenylpropane-1,3-diol, was applied in the diethylzinc addition to diphenylphosphinoyl imines to give high yields of 68-84% and excellent e.e

Full text of DOI:10.1016/S0040-4039(02)00014-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1535–1537
The first use of chiral oxazoline ligands in the highly
enantioselective diethylzinc addition to
diphenylphosphinoyl imines
Xiaomei Zhang,a Wenqing Lin,a Liuzhu Gong,a,* Aiqiao Mi,a,* Xin Cui,a Yaozhong Jiang,a
Michael C. K. Choib and Albert S. C. Chanb
aUnion Laboratory of Asymmetric Synthesis, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences,
Chengdu 610041, China
bOpen Laboratory of Chirotechnology and Department of Applied Biology and Chemical Technology,
The Hong Kong Polytechnic University, Hong Kong, China
Received 23 October 2001; revised 11 December 2001; accepted 20 December 2001
Abstract—A series of chiral oxazolines, which had been conveniently prepared from commercially available (1S,2S)-2-amino-1-
phenylpropane-1,3-diol, was applied in the diethylzinc addition to diphenylphosphinoyl imines to give high yields of 68–84% and
excellent e.e. values of 90–93%. © 2002 Published by Elsevier Science Ltd.
1a, R= Ph
1b, R= iPr
Optically active amines are very important intermedi-
ates for the synthesis of some natural products, physio-
Ph
O
O
O
1c, R= Naph
1d, R= Bn
logically active substances and pharmaceutical
compounds.1 They are also extensively used as resolv-
ing reagents and chiral auxiliaries in asymmetric synthe-
sis.2 For all of these reasons, many methods for the
asymmetric synthesis of chiral amines have been devel-
oped.1,3,4 Other than the enantioselective reduction of
prochiral imines and enamides,3,4 the asymmetric addi-
tion of nucleophiles to imines is one of the most
convenient methodologies for this purpose.5 Highly
enantioselective addition of diethylzinc to imines lead-
ing to optically active amines is attracting increasing
attention.6 Although many chiral ligands have been
prepared for this transformation, most of them are
limited to the derivatives of chiral aminoalcohols.6a–f
To date, the most efficient ligands for this transforma-
tion are the conformationally restricted and structurally
rigid aminoalcohols, but they suffer from the inconve-
nience associated with their multi-step syntheses.6e To
find more efficient and easily prepared ligands for this
addition, families of chiral ligands with backbones
other than aminoalcohols still need to be designed.
OH
N
N
N
HO
HO
Ph
Ph
R
1e, R=CH2Naph
1
1f
2
Chiral oxazolines with a backbone similar to that found
in 1 have three structural characteristics that might
enable them to be the promising candidates in competi-
tion with aminoalcohols in catalyzing the diethylzinc
addition of N-diphenylphosphinoylimines. (1) They
have sp2 nitrogens restricted by the oxazoline ring,
which probably makes the structure of the ligand rigid,
so that could minimize the diastereomers formed in the
transition state during catalysis. (2) The oxygen in the
oxazoline ring is conjugated with CꢀN, which causes
the nitrogen to be more Lewis basic so that would
change the Lewis acidity and catalytic activity of their
zinc complexes. (3) The chiral environment could be
systematically modified for the high enantioselectivity
by fine-tuning the size of the R groups in 1. To the best
of our knowledge the use of chiral oxazolines in asym-
metric diethylzinc addition to imines has not been
presented so far. Herein, we would like to report their
first application in the titled reaction.
Keywords: diethylzinc addition; imines; oxazolines.
* Corresponding authors. Tel.: 86-28-5257883; fax: 86-28-5223978;
e-mail: gonglz@cioc.ac.cn; miaq@cioc.ac.cn
The preparation of 1 and 27a starting from commer-
cially available compounds (1S,2S)-2-amino-1-phenyl-
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)00014-X

1536
X. Zhang et al. / Tetrahedron Letters 43 (2002) 1535–1537
As we expected, this set of chiral oxazoline ligands was
efficient and highly enantioselective for the titled reac-
tion. Enantioselectivities higher than 84% e.e. were
induced by most of the oxazolines 1 (entries 1–5). The
chiral carbon bonded to the hydroxyl group in the ligand
was very important for achieving high enantioselectivity.
Without this chiral center, oxazoline 2 gave a very low
enantioselectivity of 23% e.e. (entry 7). The configuration
of the product was also controlled by the chiral carbon
bonded to the hydroxyl group. When the configuration
of this carbon was inverted, but that of the carbon
bonded to nitrogen in the oxazoline ring maintained, as
exemplified by 1a and 1f, the configuration of the product
6a was inverted from S to R (entries 1 and 6); however,
the enantioselectivity decreased slightly to 76% e.e.
Varying the size of the R group resulted in a slight effect
on the enantioselectivity (entries 1–5). Chiral oxazoline
ligand 1a in which R was a phenyl group showed the
highest level of chiral induction for the diethylzinc
addition to imine 5a, giving an e.e. of 91%.
propane-1,3-diol (3) according to the known procedure
with minor modification is shown in Scheme 1.7b The
chiral oxazoline 1f was prepared from 1a by a Mitsunobu
configuration inversion procedure in 20% yield (Scheme
2), in order to investigate the effect of chiral carbon
bonded to hydroxyl group on the enantioselectivity.8
First, the different chiral oxazolines 1 and 2 were
examined for the addition of diethylzinc to N-
diphenylphosphinoyl benzalimine (5a) leading to
diphenylphosphinoylamide 6a to find the optimal ligand.
The results of imine 5a reacting with Et2Zn in the
presence of stoichiometric amounts of 1 and 2 in toluene
at room temperature are summarized in Table 1.
The utility of the optimal oxazoline 1a as a promotor in
diethylzinc addition to various aromatic imines 5a–g was
also investigated. As can be seen in Table 2, all of the
reactions worked smoothly to give the corresponding
amides in high yields (68–84%) and excellent e.e.’s
(90–93%).
Scheme 1. Reagents and conditions: (a) RCOCl or (PhCO)2O
(1 equiv.), Et3N, THF, rt; (b) TsCl (1 equiv.), Et3N, CH2Cl2,
reflux, 51–80%.
In conclusion, a series of chiral oxazolines were conve-
niently synthesized from commercial material. Their
application in catalyzing diethylzinc addition to aromatic
N-diphenylphosphinoylimines led to high yields and
excellent e.e. values of 90–93%. The configuration of the
product was controlled by the chirality of the carbon
bonded to the hydroxyl group in the oxazoline. This first
successful example using chiral oxazolines to promote the
COOH
a, b
O
+
O
N
HO
N
HO
Ph
Ph
NO2
1a
1f
Scheme 2. Reagents and conditions: (a) Ph3P, DEAD, THF,
reflux; (b) K2CO3, CH3OH, rt, 20% (two steps).
Table 2. Asymmetric diethylzinc addition to aromatic N-
diphenylphosphinoyl imines (5a–g) promoted by oxazoline
1aa
Table 1. Enantioselective diethylzinc addition of
N-diphenylphosphinoyl benzalimine (5a) in the presence of
the chiral oxazolines 1 and 2a
O
O
O
PPh2
PPh2
O
N
HN
O
PPh2
1 or 2
N
HO
+
Et2Zn
Ph
PPh2
*
N
1a
Ph
H
toluene, rt
Ph
HN
+
Et2Zn
5a
6a
*
Ar
H
toluene, rt
Ar
5
6
Entry
Ligands
Yield (%)b
e.e. (%)c
Config.d
Ar
Ph
Imine
Yield (%)b
e.e. (%)c
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
2
77
62
79
70
65
56
55
91
85
85
87
84
76
23
S
S
S
S
S
R
S
5a
5b
5c
5d
5e
5f
77
82
83
84
72
68
75
91
92
90
90
93
93
90
p-ClC6H4-
p-Br-C6H4-
p-CH3OC6H4-
p-CH3C6H4-
m-CH3C6H4-
Piperonyl
a The reaction was carried out at room temperature in the presence of
a stoichiometric amount of oxazoline for 48 h.9
b Isolated yield based on imine.
5g
a All reactions were carried out according to the procedure presented
in Ref. 9.
c Determined by HPLC.
b Isolated yields based on imines.
c Determined by HPLC.
d Determined by comparison of the retention time with literature
values.6

X. Zhang et al. / Tetrahedron Letters 43 (2002) 1535–1537
1537
titled reaction implies that a large family of chiral
compounds containing an oxazoline ring moiety have
the potential, and could be developed for promoting
the highly enantioselective dialkylzinc addition to N-
diphenylphosphinoylimines.
6. (a) Soai, K.; Hatanaka, T.; Miyazawa, T. J. Chem. Soc.,
Chem. Commun. 1992, 1097; (b) Andersson, P. G.; Gui-
jarro, D.; Tanner, D. Synlett 1996, 727; (c) Andersson, P.
G.; Guijarro, D.; Tanner, D. J. Org. Chem. 1997, 62, 7364;
(d) Guijarro, D.; Pinho, P.; Andersson, P. G. J. Org.
Chem. 1998, 63, 2530; (e) Brandt, P.; Hedberg, C.;
Lawonn, K.; Pinho, P.; Andersson, P. G. Chem. Eur. J.
1999, 5, 1692; (f) Jimeno, C.; Reddy, K. S.; Sola, L.;
Moyano, A.; Pericas, M. A.; Riera, A. Org. Lett. 2000, 2,
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Cui, X.; Jiang, Y. Z.; Choi, M. C. K.; Chan, A. S. C.
Tetrahedron Lett. 2001, 42, 6369.
Acknowledgements
We are grateful for financial support from the National
Science Foundation of China (20102005) and The
Hong Kong Polytechnic University ASD Fund.
7. (a) Rozwadowska, M. D. Tetrahedron: Asymmetry 1998, 9,
1615; (b) Poelert, M. A.; Hulshof, L. A.; Kellogg, R. M.
Recl. Trav. Chim. Pays-Bas 1994, 113, 355.
8. (a) Mitsunobu, O. Synthesis 1981, 1; (b) Hughes, D. L.
Org. Prep. Proc. 1996, 28, 127.
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9. Typical experimental procedure for the enantioselective
addition of diethylzinc to N-diphenylphosphinoyl benzal-
imine (5a) in the presence of 1a: Imine 5a (30.5 mg, 0.1
mmol) and oxazoline 1a (25.3 mg, 0.1 mmol) were dis-
solved in toluene (1.5 mL) under argon. To the mixture
was added Et2Zn in hexane (1 M, 0.5 mL, 0.5 mmol) at rt.
After stirring for 48 h, the reaction was quenched with
saturated aqueous ammonium chloride, and the aqueous
layer was extracted with CH2Cl2. The combined organic
layer was washed with brine, and dried over anhydrous
Na2SO4. After evaporation of the solvent, the residue was
purified through column chromatography on silica gel to
give 6a (25.8 mg, 0.077 mmol, 77%) as a white solid. The
enantiomeric excess of the S-isomer 91% (major) was
determined by HPLC (Chiracel AD column, hexane/
propan-2-ol=80:20; flow rate 1 mL/min; R-isomer, tR
13.17 min and S-isomer, tR 17.82 min).