Highly enantioselective 1,4- addition of diethyl phosphite to enones using a dinuclear Zn catalyst

Article abstract of DOI:10.1002/chem.200802688

An experiment was conducted to show highly enantioselectivities 1,4-addition of diethyl phosphite to enones through dinuclear zinc catalyst. The use of diethylzinc in combination with chiral ligands such as amino alcohols effectively led to chiral inducti

Full text of DOI:10.1002/chem.200802688

DOI: 10.1002/chem.200802688
Highly Enantioselective 1,4-Addition of Diethyl Phosphite to Enones Using a
Dinuclear Zn Catalyst
Depeng Zhao,[a] Ye Yuan,[a] Albert S. C. Chan,[b] and Rui Wang*[a, b]
Chiral phosphonates and their phosphonic acid deriva-
tives have attracted intense interest[1] in recent years due to
their potential biological activity.[2] The asymmetric conju-
gate addition of phosphites to electron-deficient olefins pro-
vides a convenient and direct route toward functionalized
chiral phosphonates.[3] In contrast, only a few catalytic asym-
metric strategies for this transformation have been devel-
oped.[4,5] Very recently, Wang and co-workers[4a] described
the first enantioselective 1,4-addition reactions of diphenyl
phosphite to nitroalkenes with cinchona alkaloid[6] catalysts.
Subsequently, Terada and co-workers[4b] also provided a
straightforward organocatalytic approach for the phospha-
Michael addition of nitroalkenes by employing a highly effi-
cient chiral guanidine[7] catalyst. In addition, Jørgensen and
co-workers[4c] reported an organocatalytic enantioselective
phosphonylation of enals, and suscessfully applied the Mi-
chael adducts to the synthesis of biologically important com-
pounds. However, to the best of our knowledge, the catalytic
asymmetric phospha-Michael addition of enones has never
been reported to date, despite the powerful synthetic poten-
tial of the phosphorus adducts. Herein, we report the first
catalytic asymmetric 1,4-addition of diethyl phosphite to
enones by using a dinuclear zinc catalyst.
Table 1. Optimization of the catalytic asymmetric hydrophosphonylation
of enones.
Entry[a]
L
Et2Zn
[mol%]
2
Solvent
Yield
[%][b]
ee
([mol%])
N
[%][c]
1
2
3
–
150
20
150
150
150
40
40
40
40
40
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
toluene
toluene
toluene
toluene
toluene
toluene
THF
75
41
60
78
80
54
trace
trace
65
91
98
90
55
–
0
À25
À40
À5
75
L1 (20)
L1 (20)
L1 (20)
L2 (20)
L2 (20)
L2 (20)
L2 (20)
L2 (20)
L2 (20)
L2 (20)
L2 (10)
L2 (20)
L2 (20)
4[d]
5
6
7
8
9
10
11[f]
12[f]
13[f]
14[f]
n.d.[e]
n.d.[e]
55
35
99
95
99
79
CH2Cl2
Et2O
hexane
toluene
toluene
toluene
toluene
Initially, it was found that diethylzinc was able to promote
the addition of diethyl phosphite to enone 1a (Table 1,
entry 1). This process might be achieved by deprotonation
of the phosphite to generate a highly nucleophilic zinc phos-
phonate intermediate.[8] Inspired by this finding, we hy-
40
20
40
40
60
[a] Reactions were carried out with 1a (0.25 mmol) and 2 (1.5 equiv) in
2.5 mL solvent at room temperature for 12 h unless otherwise noted.
[b] Yield of isolated product. [c] The enantiomeric excess was determined
by HPLC on a chiralcel OD-H column. [d] The reaction was carried out
at 08C. [e] Not determined. [f] 4 A molecular sieves were used as an ad-
ditive.
[a] D. Zhao, Dr. Y. Yuan, Prof. R. Wang
State Key Laboratory of Applied Organic Chemistry and Institute of
Biochemistry and Molecular Biology, School of Life Sciences
Lanzhou University, Lanzhou 730000 (China)
Fax : (+86)931-891-2567
pothesized that diethylzinc in combination with chiral li-
gands such as amino alcohols[9] might lead to chiral induc-
tion for the current transformation. Thus L1 was selected to
examine the postulation. However, even in the best case,
the enantioselectivity was poor (40% ee) owing to a side re-
action (Table 1, entry 4).[10] Frustrated by these results, we
E-mail: wangrui@lzu.edu.cn
[b] Prof. A. S. C. Chan, Prof. R. Wang
Department of Applied Biology and Chemical Technology
The Hong Kong Polytechnic University (Hong Kong)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200802688.
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Chem. Eur. J. 2009, 15, 2738 – 2741

COMMUNICATION
Table 2. Substrate scope for the catalytic asymmetric hydrophosphonyla-
tion of enones.
set out to screen for an efficient system that would avoid
the competitive background reaction.
Recently, a dinuclear zinc catalyst developed by Trost and
co-workers has emerged as a powerful asymmetric catalyst
for many enantioselective reactions.[11] The dinuclear zinc
catalyst formed from L2 and diethylzinc is thought to func-
tion in a dual Lewis acid/Lewis base manner. In light of
these results, we further speculated that this bifunctional
catalyst might lead to the formation of a zinc phosphonate
intermediate and catalyze the asymmetric phospha-Michael
addition reaction. Fortunately, when the dinuclear zinc cata-
lyst was introduced to the reaction, the enantiomeric excess
increased remarkably to 75% ee (Table 1, entry 6). Solvent
screening indicated that toluene was the best solvent for this
reaction among those examined with respect to enantiose-
lectivity. To our great delight, when 4 ꢁ molecular sieves
were added to the reaction, the conversion and enantiose-
lectivity were significantly enhanced; the desired phospha-
Michael adduct 3a was obtained in 98% yield and 99% ee
(Table 1, entry 11). A slight decrease of enantioselectivity
and reactivity was observed when the loading of L2 was re-
duced from 20 mol% to 10 mol% (Table 1, entry 12). Other
dialkyl phosphites were also investigated. When dimethyl
phosphite was employed as a nucleophile, a low yield was
observed (Table 1, entry 13). Switching diethyl phosphite to
diisopropyl phosphite bearing bulkier alkyl groups led to a
deterioration in both yield and enantioselectivity (Table 1,
entry 14).
Entry[a]
1
R
Ar
Product
[%][b]
ee
[%][c]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1 f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3a (98)
3b (94)
3c (92)
3d (80)[d]
3e (98)
3 f (90)
3g (99)
3h (89)
3i (95)
3j (99)
3k (93)
3l (86)[e]
3m (85)[e]
3n (96)
3o (99)
3p (93)
3q (99)
3r (94)
99
98
98
94
97
96
93
97
96
95
96
93
95
99
96
99
94
98
3-MeC6H4
4-MeC6H4
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
4-FC6H4
3-ClC6H4
4-ClC6H4
4-BrC6H4
4-CNC6H4
1-naphthyl
2-naphthyl
Ph
9
10
11
12
13
14[f]
15
16
17
18
Ph
4-MeOC6H4
4-ClC6H4
Ph
Ph
Ph
Ph
2-furyl
iPr
nBu
[a] Reactions were carried out with 1 (0.25 mmol) and 2a (1.5 equiv) in
2.5 mL toluene at room temperature for 12 h unless otherwise noted.
[b] Yield of isolated product. [c] The enantiomeric excess was determined
by HPLC analysis (see the Supporting Information). [d] Reaction stirred
for 36 h. [e] Reaction stirred for 24 h. [f] The absolute configuration of
3n was determined to be S by chemical correlation.
Under these optimized reaction conditions (20 mol% of
L2/Et2Zn and 4 ꢁ MS in toluene at room temperature), a
series of enones were investigated in the asymmetric phos-
pha-Michael addition reaction. As illustrated in Table 2,
consistently excellent enantioselectivities were observed for
a broad range of enones. b-Aryl substituted enones with var-
ious substituents all afforded 1,4-adducts with excellent
enantioselectivities (Table 2, entries 1–15). b-Heteroaromat-
ic and b-aliphatic enones[12] were also excellent substrates
for the present transformation (Table 2, entries 16–18). All
enones underwent the phospha-Michael addition reaction
smoothly to give the corresponding products in high yields.
By comparison, enones with an ortho-substituted phenyl
(Table 2, entry 4) or a naphthyl (Table 2, entries 12, 13) at
the b-position showed a slightly reduced reactivity due to
the steric hindrance.
The absolute configuration of compound 3n was deter-
mined by chemical correlation with a known compound as
follows. The Baeyer–Villiger oxidation of 3n with CF3CO3H
afforded the corresponding triester 4 without a loss in enan-
tioselectivity (99% ee). Then compound 4 was hydrolyzed
to give (S)-3-phenyl-3-phosphonopropanoic acid 5 of known
absolute configuration (Scheme 1).[13] By comparison of the
optical rotation, the absolute configuration of compound 3n
was determined to be S. The rest of the products were tenta-
tively assigned by analogy.
Scheme 1. Determination of the absolute configuration of compound 3n.
volves deprotonation of diethyl phosphite by the catalyst to
form the zinc phosphonate intermediate. Then the enone co-
ordinates with another zinc of this catalyst and undergoes
the phospho-transfer. The product is released by a proton
exchange with the next diethyl phosphite and the catalyst is
regenerated.
In conclusion, we have demonstrated the first asymmetric
1,4-addition reaction of diethyl phosphite with simple
enones catalyzed by a dinuclear zinc complex. The g-oxo-
phosphonates were obtained in a straightforward manner in
high yields with excellent enantioselectivities (up to 99%
ee). Furthermore, this new catalytic phospha-Michael addi-
tion reaction was screened for a broad range of enones bear-
ing both aryl and alkyl b-substituents. The strategy makes
the asymmetric synthesis of biologically active phosphonates
Although the detailed reaction mechanism remains un-
clear, a plausible mechanism is postulated based on the ob-
served results (Scheme 2). The initial step of this cycle in-
Chem. Eur. J. 2009, 15, 2738 – 2741
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R. Wang et al.
Keywords: asymmetric
hydrophosphosphonylation
phosphonates
catalysis
·
enones
addition
·
·
·
Michael
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Scheme 2. Proposed catalytic cycle of the phospha-Michael addition.
and derivatives thereof more accessible. Further investiga-
tion of the detailed reaction mechanism and synthetic meth-
odology are in progress.
Experimental Section
Typical experimental procedure: Diethylzinc (0.1 mL, 1m in toluene,
0.1 mmol) was added to a stirred solution of L2 (32 mg, 0.05 mmol) in
toluene (0.5 mL) under an argon atmosphere. The mixture was stirred at
room temperature for 0.5 h to generate the zinc catalyst. The resulting
solution of catalyst was then added by syringe to a stirred and cooled
(08C) mixture of 4 ꢁ molecular sieves (100 mg, dried at 2008C under
vacuum for 12 h), (E)-chalcone (52 mg, 0.25 mmol), and diethyl phos-
phite (48 mL, 0.375 mmol) in toluene (2 mL) under an argon atmosphere.
After the addition, the mixture was allowed to warm to room tempera-
ture and stirred for 12 h. The reaction was cooled to 08C and quenched
with aqueous HCl (1m). The mixture was extracted with CH2Cl2, and the
organic layer was washed with saturated NaHCO3 and brine, dried over
Na2SO4, and concentrated under vacuum. The pure product was afforded
by column chromatography on silica gel (petroleum ether/ethyl acetate
7:1–1:2).
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We are grateful for the grants from the National Natural Science Founda-
tion of China (Nos. 20525206, 20621091, 90813012, and 20772052) and
the Chang Jiang Program of the Ministry of Education of China for fi-
nancial support.
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Asymmetric 1,4-Addition of Diethyl Phosphite to Enones
COMMUNICATION
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Received: December 19, 2008
Published online: February 11, 2009
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