Enantioselective addition of diethylzinc to aromatic aldehydes catalyzed by 14-hydroxylsubstituted morphinans

Article abstract of DOI:10.1016/j.tetasy.2008.07.031

Enantioselective addition reactions of diethylzinc to aromatic aldehydes were performed with catalytic amounts of 14-hydroxylsubstituted morphine alkaloids. The reaction conditions such as catalyst loading, time and temperature were optimized to obtain the highest enantiomeric excess. Optically active secondary alcohols were synthesized with ee up to 95%.

Full text of DOI:10.1016/j.tetasy.2008.07.031

Tetrahedron: Asymmetry 19 (2008) 1970–1972
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Enantioselective addition of diethylzinc to aromatic aldehydes catalyzed by
14-hydroxylsubstituted morphinans
b,
a
b
c
Minoo Dabiri a, , Peyman Salehi , Gholamreza Kozehgary , Seddigheh Heydari , Akbar Heydari ,
*
*
Maryam Esfandyari c
a Department of Chemistry, Faculty of Science, Shahid Beheshti University, G. C., Evin, Tehran 1983963113, Iran
b Department of Phytochemistry, Medicinal Plants and Drugs Research Institute, Shahid Beheshti University, G. C., Evin, Tehran 1983963113, Iran
c Department of Chemistry, Tarbiat Modarres University, P.O. Box 14155-4838, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Enantioselective addition reactions of diethylzinc to aromatic aldehydes were performed with catalytic
amounts of 14-hydroxylsubstituted morphine alkaloids. The reaction conditions such as catalyst loading,
time and temperature were optimized to obtain the highest enantiomeric excess. Optically active second-
ary alcohols were synthesized with ee up to 95%.
Received 6 July 2008
Accepted 29 July 2008
Available online 28 August 2008
Ó 2008 Published by Elsevier Ltd.
1. Introduction
Wells et al. have reported the application of codeine and oxyco-
done modified platinum surfaces in the asymmetric hydrogenation
Chiral ligands are important tools for the synthesis of enantio-
pure organic compounds.1 An easy to perform and well-docu-
mented reaction for testing the catalytic reactivity and enantio-
differentiating ability of certain catalytic systems is the addition
of diethylzinc to aromatic aldehydes.2 In particular, many chiral
b-aminoalcohols, both natural and synthetic, have been tested in
this addition with varying degrees of success. High enantioselectiv-
ities have been achieved by using compounds such as 3-exo-
(dimethylamino) isoborneol (DAIB) or derivatives of ephedrine,
norephedrine, quinine and other alkaloids (Fig. 1).3–9 Chiral alka-
loids have been extensively used in asymmetric synthesis.10 How-
ever, morphine alkaloids have rarely been used as ligands in
asymmetric reactions.
of methyl pyruvate and butane-2,3-dione.11 However, very low
ee’s of up to 15% were obtained.
Herein, we report the enantioselective alkylation of aromatic
aldehydes by diethylzinc in the presence of catalytic amounts of
14-hydroxylsubstituted morphine alkaloids, oxycodone 1, 14-
hydroxy codeinone 2 and naltrexone 3 (Fig. 2). To the best of our
knowledge, morphinans have not been used as chiral ligands for
the enantioselective addition of dialkylzinc to aldehydes.
CH3
CH3
N
N
OH
O
N
OH
OH
O
O
O
O
O
OCH3
OCH3
OH
HO
N
1
2
3
OH
H3CO
Figure 2.
NR1R2
2. Results and discussion
quinine and quinidine
ephedrine and norephedrine
Chiral ligands 1–3 were synthesized according to the literature
procedure.12–15 Enantioselective addition of diethylzinc to aro-
matic aldehydes was investigated in the presence of catalytic
amounts of 1–3 (Scheme 1).
Figure 1. Alkaloids used as ligands in the enantioselective addition of dialkylzinc to
aldehydes.
First, the effect of temperature and catalyst loading on the reac-
tion of diethylzinc to benzaldehyde was examined (Table 1). It was
* Corresponding authors. Tel.: +98 98 21 22431663 (M.D.).
E-mail addresses: m-dabiri@sbu.ac.ir (M. Dabiri), p-salehi@sbu.ac.ir (P. Salehi).
0957-4166/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2008.07.031

M. Dabiri et al. / Tetrahedron: Asymmetry 19 (2008) 1970–1972
1971
Although ligand 2 gave higher yields under the same conditions
(+10 °C, 10 mol % of the catalyst for 40 h) than 1, better ee’s were
obtained with ligands 1 and 3 (Table 1, entries 3, 8, and 15). Treat-
ment of 3 with 120 mol % of titanium isopropoxide led to a signif-
icant decrease of the enantioselectivity with an opposite
configuration (entry 18).
H
HO
Chiral catalyst (10 mol%)
Ar-CHO
+
Et2Zn
Ar
Toluene/Hexane
Scheme 1.
Therefore, ligands 1 and 3 were used as the catalysts of choice
for the addition of diethylzinc to other aromatic aldehydes (Table
2). At first, the reactions were performed using 10 mol % of the cat-
alyst in toluene at À20 °C.
observed that lower temperatures and high catalyst loading gave
higher enantioselectivities. A comparison between the abilities of
all three catalysts under different conditions is summarized in
Table 1. As shown, higher ee’s were obtained using 1 and 3 at lower
temperatures (Table 1, entries 5, 6, 16, and 17). It should be
As shown in Table 2, the electronic effects of the aromatic ring
substituents also played an important role with regard to the
enantioselectivity but not the yield of the reactions. Lower enantio-
selectivities were obtained in the presence of electron-donating
substituted groups (Table 2, entries 8–10). The presence of ortho
substituents lowered the enantioselectivity of the reactions (Table
2, entries 9–11).
emphasized that the
a,b-unsaturated carbonyl function of the
ligand 2 was stable to diethylzinc under the reaction conditions.
When a mixture of ligand 2 and 3 equiv of diethylzinc was stirred
at room temperature for 40 h, compound 4 was not obtained
(Scheme 2).
Table 2
Table 1
Enantioselective addition of diethylzinc to aromatic aldehydes catalyzed by ligands 1
Enantioselective addition of diethylzinc to benzaldehyde catalyzed by chiral ligands
1–3
and 3a
Entry
Aldehyde
Ligand
Yieldb (%)
eec,d (%)
Entry
Ligand
(mol %)
T
(°C)
Additive
Yielda
(%)
eeb
(%)
Configurationc
1
2
3
4
5
6
7
8
9
p-FC6H4CHO
p-FC6H4CHO
1
3
1
3
1
1
3
1
1
1
1
83 (92)e
(84)e
98 (95)e
(97)e
98 (88)e
66
67 (81)e
(95)e
68 (78)e
(93)e
66 (71)e
53
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
1 (1)
1 (5)
+10
+10
+10
+10
À20
À30
+30
+10
+10
À20
+10
+10
À10
À30
+10
À20
À30
+10
+10
—
—
—
35
45
55
50
50
75
91
80
75
32
72
75
41
43
75
65
60
55
46
—
9
35
2
58
80
7
28
66
15
33
17
50
53
71
80
89
16
38
—
p-ClC6H4CHO
p-ClC6H4CHO
p-BrC6H4CHO
p-MeC6H4CHO
p-MeC6H4CHO
p-MeOC6H4CHO
o,p-(MeO)2C6H3CHO
o-MeOC6H4CHO
o-ClC6H4CHO
(S)
(S)
(R)
(S)
(S)
(R)
(R)
(S)
(S)
(S)
(S)
(R)
(R)
(S)
(S)
(S)
(R)
(R)
1 (10)
1 (10)
1 (10)
1 (20)
2 (10)
2 (10)
2 (10)
2 (10)
2 (10)
2 (10)
2 (10)
2 (10)
3 (10)
3 (10)
3 (20)
3 (10)
3 (10)
Benzoic acidd
—
—
—
—
(73)e
70
74
87
97
(93)e
32
50
32
45
Benzoic acidd
10
11
Benzoic acidd
Phthalic acidd
a
Conditions: À20 °C, 40 h and 10 mol % of ligand.
Acetic acidd
b
c
Measured as conversion % by GC.
—
—
—
—
—
Determined by capillary chiral GC analysis using the chiral column (HP-chiral).
Absolute configuration was determined by comparing the sign of specific
d
rotation.16–19 The major enantiomer in all cases had the (S)-configuration.
e
Values in parentheses are for conditions: À30 °C, 40 h and 20 mol % of ligand.
e
Ti(OPri)4
Benzoic acidd
When the amount of ligand was increased to 20 mol %, and the
temperature was decreased to À30 °C, the adduct was obtained in
high yield and good enantiomeric excess (Table 1, entries 6, 17 and
Table 2, entries 1–5, 7). Although ligand 1 gave higher yields than
3, better enantioselectivities were obtained with 3 (Table 1, entries
6, 17 and Table 2 entries 1, 2).
a
GC yield on the mixture of the two enantiomers.
Ee was determined by GC using a chiral capillary column (HP-Chiral).
Absolute configuration of the major enantiomer was determined by comparison
b
c
with authentic samples.
d
10 mol % of the acid were added.
e
In the presence of 120 mol % of Ti(OPri)4.
3. Conclusion
CH3
N
CH3
Et
OH
N
OH
O
In conclusion three morphinan ligands have been used for the
first time in the enantioselective addition of diethylzinc to aro-
matic aldehydes. These results demonstrate that the chiral morphi-
nan-based ligands are promising in asymmetric catalysis and
deserve certainly more attention.
Et2Zn, 40h
X
O
O
O
Toluene/Hexane
OCH3
OCH3
4
2
4. Experimental
4.1. General
14-Hydroxy codeinone
Scheme 2.
Mass spectra were recorded on a FINNIGAN-MAT8430 mass
spectrometer operating at an ionization-potential of 70 eV. Con-
versions were determined with a Hewlett-Packard HP-5890 GC
instrument equipped with a flame ionization detector and a 30 m
HP-1 capillary column, using nitrogen (2 mL/min) as carrier gas.
The enantiomeric ratios were determined with the aforementioned
apparatus using a 30 m WCOT fused silica capillary column (HP-
chiral).
The addition of catalytic amounts (10 mol %) of benzoic acid in
the reaction of diethylzinc to benzaldehyde with 2 led to a signif-
icant increase in the ee%, while with 1 and 3 led to a decrease in the
enantioselectivity (Table 1, entries 4, 9, and 19). In each case, the
product was obtained with an opposite configuration. Mass spec-
trometric studies showed that the by-product 4 was produced
in situ in low yield in the presence of benzoic acid.

1972
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The ligand (0.11 mmol) was placed in a test tube and dissolved
in dry toluene (2 mL). The solution was stirred for 5 min. A 1.0 M
solution of diethylzinc in n-hexane (2.2 mmol, 2.2 mL) was then
added, and after the mixture had been stirred for 5 min, a solution
of benzaldehyde (1.11 mmol) in dry toluene (1 mL) was added by
syringe. The mixture was stirred at the appropriate temperature
for 40 h. Saturated aqueous NH4Cl was added (10 mL) and the mix-
ture was extracted with ethyl acetate (3 Â 20 mL). The collected
organic phase was washed with water, dried over Na2SO4 and ana-
lyzed by GC, after suitable dilution.
Acknowledgment
Financial support from the Research Council of Shahid Beheshti
University is gratefully acknowledged.
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