Enantioselective alkynylation of aromatic aldehydes catalyzed by new chiral oxazolidine ligands

Article abstract of DOI:10.1016/j.tetlet.2004.11.165

New chiral oxazolidines were conveniently synthesized from natural amino acids in three simple steps with good yields. The use of chiral oxazolidine ligands for the enantioselective alkynylation of aldehydes provides a simple, practical and inexpensive me

Full text of DOI:10.1016/j.tetlet.2004.11.165

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 863–865
Enantioselective alkynylation of aromatic aldehydes catalyzed
by new chiral oxazolidine ligands
b
a,b
Yong-feng Kang,a,b Rui Wang,a,b, Lei Liu, Chao-shan Da,
*
Wen-jin Yana,b and Zhao-qing Xua,b
aState Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics,
Chinese Academy of Sciences, Lanzhou, Gansu 730000, China
bDepartment of Biochemistry & Molecular Biology, School of Life Sciences, Lanzhou University, Lanzhou, Gansu 730000, China
Received 3 September 2004; revised 18 November 2004; accepted 24 November 2004
Available online 18 December 2004
Abstract—New chiral oxazolidines were conveniently synthesized from natural amino acids in three simple steps with good yields.
The use of chiral oxazolidine ligands for the enantioselective alkynylation of aldehydes provides a simple, practical and inexpensive
method to generate chiral propargyl alcohols with 85–99% ee.
Ó 2004 Elsevier Ltd. All rights reserved.
The enantioselective alkynylzinc addition to ketones1 or
aldehydes2 is a very useful method for the synthesis of
chiral propargyl alcohols, which are important versatile
building blocks of many biologically active compounds
and natural products.3 Since Ishizaki and Hoshino re-
ported the first addition of alkynylzinc reagents to alde-
hydes in 1994,4 some chiral ligands, such as N-methyl
ephedrine,5 sulfonamide alcohol,6 BINOL and its deriva-
tives,7 have successfully been applied in this reaction in
recent years. Other chiral compounds, such as disulfide-
oxazolidine,8 have also been used, but in low enantio-
selectivity (36–60% ee). Herein we report the discovery
of a new chiral oxazolidine ligand for the asymmetric
addition of terminal acetylenes to aromatic aldehydes
with high ee values under mild and convenient condition.
Mukaiyama-aldol reactions,12 the carbonyl-ene reac-
tions13 and others.14 Based on the results of our recent
report on catalytic asymmetric addition of alkynylzinc
to aldehydes,6,15 we think that the chiral oxazolidine
ligands can also catalyze the asymmetric addition of
alkynylzinc to aldehydes.
From commercially available cheaper starting materials,
oxazolidine ligands 2a–d were prepared in three simple
steps (Scheme 1).14a,c,16,17 After the typical methyl ester-
ation of amino acids, the amino methylesters were trea-
ted with excess amount of phenylmagnesium bromide or
ethylmagnesium bromide to give the corresponding
amino alcohols 1a–d. Compounds 1a–d were treated
˚
with excess amount of acetone and 4 A MS to afford
the corresponding oxazolidines 2a–d in 52–66% overall
yields.
The oxazoline ligands derived from the natural amino
acids have become a series of important molecules in
asymmetric catalysis because of its easy availability
and low cost. The direct use of the oxazoline ligands
in combination with metal salts in asymmetric catalysis
has resulted in a series of exciting discoveries. Among
these there are the Diels–Alder reactions,9 the oxidation
reactions,10 the cyclopropanation reactions,11 the
1
R2
R2
R
R1
R1
R2
R2
COOH
c
a
b
O
HN
NH2
OH
H2N
1a-1d
2a: R1=iPr, R2=phenyl,yield : 62%
2a-2d
2b: R1=iBu, R2=phenyl, yield : 52%
2c: R1=Bn, R2=ethyl, yield : 60%
2d: R1=Bn, R2=phenyl, yield : 66%
Keywords: Aldehydes; Alkynes; Oxazolidines; Addition; Asymmetric
catalysis.
Scheme 1. Preparation of oxazolidine from amino acids. Reagents and
conditions: (a) MeOH, SOCl2, ꢀ30 °C, to rt, then reflux for 2 h; (b)
*
Corresponding author. Tel.: +86 931 891 2567; fax: +86 931 891
2561; e-mail: wangrui@lzu.edu.cn
˚
PhMgBr or EtMgBr, THF, rt, 24 h; (c) acetone, 4 A MS, rt, 24 h.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.165

864
Y. Kang et al. / Tetrahedron Letters 46 (2005) 863–865
Table 2. Asymmetric addition phenylacetylene to aromatic aldehydes
promoted by ligand 2da,b
OH
Ph
ZnEt2, 2
Ph
PhCHO
Ph
+
solvent
Aldehydes
Time (h) Isolated yield (%) eec (%)
Benzaldehyde
24
48
48
48
48
24
75
66
68
70
74
60
77
74
70
76
78
71
93/Rd
87
Scheme 2. Asymmetric addition phenylacetylene to benzaldehyde.
3-Tolualdehyde
4-Tolualdehyde
3-Anisaldehyde
4-Anisaldehyde
3-Nitrobenzaldehyde
86
86
85
99
Ligands 2a–d were tested in the asymmetric addition of
phenylacetylene to benzaldehyde in the presence of
Et2Zn (Scheme 2, Table 1, entries 1–4) initially. The
results showed that ligand 2d gave the highest enantio-
selectivity among the four ligands. The oxazolidine
ligands containing a bulkier benzyl substituent on the
chiral carbon atom were found to be more effective than
those containing isopropyl or isobutyl substituents. The
replacement of the diphenyl groups on the 5,5-positions
of 2d with diethyl groups also gave low enantio-
selectivity.
3-Bromobenzaldehyde 24
4-Bromobenzaldehyde 24
2-Chlorobenzaldehyde 24
4-Chlorobenzaldehyde 24
4-Fluorobenzaldehyde 24
90
91
85
88
93
85
b-Naphthaldehyde
48
a In all of the entries: Et2Zn:phehylacetylene:aldehyde:2d = 1.4:1.4:1.0:0.1.
b All the reactions were processed under argon and at 0 °C.
c The ee values were determined by chiral HPLC with Chiracel OD
column.
d The absolute configuration is based on measurement of the optical
rotation and comparison with the literature values.8,20
The catalytic properties of ligand 2d in asymmetric
alkynylation were explored in the reaction of phenyl-
acetylene with benzaldehyde in the presence of diethyl-
zinc (Table 1, entries 4–13). We found that enantio-
selectivity of this reaction was strongly solvent dependent.
Very low ee values was obtained in toluene (entry 5),
toluene–THF (entry 7) and toluene–CH2Cl2 (entry 8).
However, there was a dramatic enhancement in enantio-
selectivity when ether or toluene–ether were used as the
solvent (entries 4 and 6). So toluene–ether was the best
solvent. We then examined the effect of the amount of
ZnEt2 on this reaction, and found decreasing the
amount of ZnEt2 from 300 to 140 mol % gave higher
ee, but further decreasing the amount of ZnEt2 to
120 mol % lead to a decrease in ee values. So the appro-
priate amount of ZnEt2 was 140 mol % (entries 4, 9–11).
We also varied the reaction temperature in order to opti-
mize the reaction condition. But, only decreased ee val-
ues were observed at either higher or lower temperatures
(entries 10, 12–13). Thus, the 0 °C condition seems most
suitable for this reaction.
Under such optimized reaction conditions of entry 10 in
Table 1, ligand 2d was employed to induce the enantio-
selective addition of phenylacetylene to a family of aro-
matic aldehydes.18,19 All propargyl alcohol derivatives
was obtained with high enantioselectivity and the ee
value was up to 99% (Table 2).
In conclusion, new chiral oxazolidines were conveniently
synthesized from natural amino acids in three simple
steps with good yields. We have demonstrated that
new chiral oxazolidine ligand 2d is an effective catalyst
for the enantioselective alkynylation of aldehydes under
mild conditions to give 85–99% ee. We provide a simple,
practical and inexpensive method to generate chiral
propargyl alcohols.
Acknowledgements
We are grateful to the National Natural Science Foun-
dation of China (Nos. 20372028, 20472026), the Minis-
try of Science and Technology of China, the Teaching
and Research Award Program for Outstanding Young
Teachers, and the Specialized Research Fund for the
Doctoral Program in Higher Education Institutions of
the Ministry of Education of China.
Table 1. Asymmetric addition phenylacetylene to benzaldehyde using
10 mol % 2 as ligands
Entry Ligands Et2Zn
(mol %)
Solvent
Temp (°C) eea (%)
1
2a
2b
2c
2d
2d
2d
2d
2d
2d
2d
2d
2d
2d
200
200
200
200
200
200
200
200
120
140
300
140
140
Tolb–ether
Tol–ether
Tol–ether
Tol–ether
Tol
0
0
0
0
0
0
0
0
0
0
0
28
68
5
2
3
4
76
29
66
32
15
82
93
73
78
80
References and notes
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D
1
mp 94–96 °C; ½aꢁ20 ꢀ128 (c 2.3, CH3CO2C2H5); H NMR
(200 MHz, CDCl3, TMS): d 1.21 (s, 3H, CH3), 1.79 (s, 3H,
CH3), 1.96 (dd, J = 10.8 Hz, J = 14.6 Hz, 1H, PhCHA),
1.88 (dd, J = 11.2 Hz, J = 15 Hz, 1H, PhCHB), 2.89 (d,
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acetylene to aldehydes: Under argon, to a solution of the
ligand 2d (0.05 mmol, 17.2 mg) in ether (4 mL), was added
a solution of Et2Zn (0.7 mmol, 1.0 M in toluene, 0.7 mL)
at room temperature. After the mixture was stirred at the
room temperature for 2 h, phenylacetylene(0.7 mmol,
76 lL) was added and the stirring continued for another
2 h. The solution was cooled to 0 °C and treated with
aldehyde (0.5 mmol, 50 lL), then the resultant mixture
was stirred for 24–48 h at 0 °C. Optically active propargyl
alcohol was obtained after acid workup and purification
by silica gel TLC.
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enantioselectivities were determined by chiral HPLC on
a Chiracel OD column and were found to be 75% (yield
60%) and 62% (yield 56%) ee, respectively.
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