Catalytic asymmetric construction of tetrasubstituted carbon stereocenters by conjugate addition of dialkyl phosphine oxides to β,β-disubstituted α,β-unsaturated carbonyl compounds

Article abstract of DOI:10.1039/c1cc16079f

The catalytic asymmetric phospha-Michael reaction of dialkyl phosphine oxides with β,β-disubstituted α,β-unsaturated carbonyl compounds was achieved. The products bearing tetrasubstituted carbon stereocenters were obtained in high yields with excellent enantioselectivities (up to >99% ee).

Full text of DOI:10.1039/c1cc16079f

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COMMUNICATION
Catalytic asymmetric construction of tetrasubstituted carbon
stereocenters by conjugate addition of dialkyl phosphine oxides to
b,b-disubstituted a,b-unsaturated carbonyl compoundsw
Depeng Zhao,b Lijuan Mao,b Linqing Wang,b Dongxu Yangb and Rui Wang*ab
Received 30th September 2011, Accepted 9th November 2011
DOI: 10.1039/c1cc16079f
The catalytic asymmetric phospha-Michael reaction of dialkyl
phosphine oxides with b,b-disubstituted a,b-unsaturated carbonyl
compounds was achieved. The products bearing tetrasubstituted
carbon stereocenters were obtained in high yields with excellent
enantioselectivities (up to 499% ee).
Due to our continuous interest in phosphorus-containing
Catalytic asymmetric construction of tetrasubstituted carbon
stereocenters is a challenging objective in chemical synthesis.1
nucleophiles and previous reports on the phospha-Michael
reaction of dialkyl phosphites and dialkyl phosphine oxides
The asymmetric conjugate addition of nucleophiles to acceptors
with a,b-unsaturated compounds,10 we began to investigate
the reaction of (E)-1,3-diphenylbut-2-en-1-one 2a with various
such as b,b-disubstituted a,b-unsaturated carbonyl compounds
is one of the most reliable approaches toward this challenge. To
phosphorus donors catalyzed by 20 mol% zinc–bis-ProPhenol
L1 complex.11 The preliminary results indicated that the
date, most studies have been focused on quaternary all-carbon
stereocenters, which have been realized by using alkyl and aryl
organometallic reagents with Cu- and Rh catalysts2,3 or by using
reactions with phosphites 1a, 1b and 1c did not proceed at
activated carbon nucleophiles such as cyanide.4 Recently, several
all in the presence of the catalyst. Surprisingly, when diallyl
studies on asymmetric conjugate boration5 and asymmetric
phosphine oxide 1d was used as the nucleophile, the reaction
epoxidation6 of b,b-disubstituted a,b-unsaturated carbonyl
compounds have been reported. By contrast, reports on building
tetrasubstituted carbon stereocenters with nucleophiles of other
elements including phosphorus nucleophiles have been much
less developed yet.7,8 This is due to the remarkably lower
reactivity of b,b-disubstituted substrates and more difficult chiral
discrimination derived from the smaller steric difference between
the b-substituents. Recently, Ye, Liang and coworkers8
reported an organocatalytic phospha-Michael reaction of
cyclic b,b-disubstituted a,b-unsaturated enones. Still, the
catalysis is ineffective to more challenging linear substrates.9
Herein, we report the first conjugate addition of dialkyl
phosphine oxides to b,b-disubstituted a,b-unsaturated enones
and N-acylpyrroles.
proceeded slowly with o10% yield at room temperature for
12 h. This is probably because that the dialkyl phosphine
oxides are more electron-rich and relatively softer nucleophiles
than dialkyl phosphites.10a,10c,12
With this result in hand, we then tried to improve the yield
of the reaction. When the reaction was performed at 60 1C, the
conversion improved a little, the product was obtained in 32%
yield with 82% ee (Table 1, entry 1). Inspired by the obtained
enantioselectivity, we then focused on the structure of the
ligand. When our previously reported thienyl-bis-ProPhenol
L2 was introduced to the present phospha-Michael reaction,
the yield and enantioselectivity were both greatly improved
(Table 1, entry 2, 74%, 99% ee). This phenomenon can be
explained by the following two points: (1) the thienyl group
will coordinate with the metal center and thereby prevent the
unfavourable binding of the Lewis basic product to the
Zn atom, which would poison the catalyst; (2) the thienyl
coordination will increase the stability of the zinc catalyst, which
might be decomposed gradually in the presence of dialkyl
phosphine oxides at high temperature. The yield seemed not
to improve upon further increase of the temperature to 60 1C.
To our delight, when pyridine was added and the solvent was
switched to toluene, the yield increased remarkably to 94% and
the reaction temperature could be reduced to 40 1C (Table 1,
entry 6). The reaction could also be performed with 10 mol%
catalyst under modified conditions despite that both the yield
and enantioselectivity were reduced (Table 1, entry 7).
a State Key Laboratory for Oxo Synthesis and Selective Oxidation,
Lanzhou Institute of Chemical Physics, Chinese Academy of
Sciences, Lanzhou, 730000, P.R. China
b Key Laboratory of Preclinical Study for New Drugs of Gansu
Province, School of Basic Medical Sciences, State Key Laboratory
of Applied Organic Chemistry, and Institute of Biochemistry and
Molecular Biology, Lanzhou University, Lanzhou,
730000, P. R. China. E-mail: wangrui@lzu.edu.cn;
Tel: +86-9318912567
w Electronic supplementary information (ESI) available: Experi-
mental procedures, analytical data (1H NMR, 13C NMR and HRMS)
for all new compounds. CCDC 842933. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/
c1cc16079f
c
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Chem. Commun., 2012, 48, 889–891 889

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Table 1 Optimization of the reaction conditions
Table 2 Scope of the phospha-Michael reaction
Entrya Substrate
R
Product Yield (%) eeb (%)
Entrya L (mol%) Solvent Additive T/1C Yieldb (%) eec (%)
1
2
Allyl
Allyl
3a
3b
94
98
99
96
1
2
3
4
5
6
7
L1 (20%) THF
L2 (20%) THF
L2 (20%) THF
L2 (20%) THF
L2 (20%) Toluene Pyridine 60
L2 (20%) Toluene Pyridine 40
L2 (10%) Toluene Pyridine 40
—
—
—
60
40
60
32
74
75
89
94
94
85
82
99
99
Pyridine 60
99d
99d
99d
94e
3
4
Allyl
Allyl
3c
3d
94
97
98
98
a
Reactions were carried out with 1d (0.375 mmol, 1.5 eq), and 2a
b
c
(0.25 mmol). Isolated yield. The enantiomeric excess was determined
d
by HPLC analysis of the isolated product. Reactions were carried out
5
6
7
8
Allyl
Allyl
Allyl
Allyl
3e
3f
94
93
94
72
96
98
96
96
e
with 1 eq of pyridine. Reaction was carried out with 1d (0.75 mmol,
1.5 eq), 2a (0.5 mmol) and 10 eq of pyridine in 2.5 mL toluene.
With the optimized reaction conditions established, the substrate
scope was then evaluated. As shown in Table 2, consistently
excellent enantioselectivities were achieved from a wide range
of b,b-disubstituted enones including aromatic- and aliphatic-
substituted substrates. The electronic nature of the substituent
on the phenyl ring did not have obvious impact on the
reaction. Interestingly, Z-2h gave the same enantiomer as
E-2h and produced higher enantioselectivity than E-2h
(Table 2, entries 8, 9). Other dialkyl phosphine oxides such
as 1e and 1f were also found to be good substrates for the
present catalysis (Table 2, entries 18, 19).
3g
3h
9
Allyl
Allyl
Allyl
3h
3i
3j
90
90
92
80
93
90
10
11
The present method was also applicable to Shibasaki’s N-
acylpyrroles4a which could serve as equivalents of b,b-disubstituted
a,b-unsaturated esters. As shown in Table 3, good yields and
excellent enantioselectivities were achieved for all aromatic and
aliphatic substrates tested. To our surprise, alkyl substrates E-5e
and Z-5e both gave high yields and enantioselectivities and
produced opposite enantiomers (Table 3, entries 5, 6).
12
13
Allyl
Allyl
3k
3l
91
97
98
98
14
15
Allyl
Allyl
3m
3n
98
84
499
499
The X-ray crystallographic result suggests that the absolute
configuration of 3q is S (Fig. 1).13 So we believe the E-enones
may adopt s-cis conformation to react with the dialkyl phosphine
oxides. In this case, the dialkyl phosphine oxide will attack the
Si-face of the enones and the stereochemistry of the final product
is S. However, for Z-enone 2h, the s-cis conformation is extremely
disfavored for the steric hindrance between the two substrates. So
Z-enone 2h has to select the s-trans conformation and thereby
providing the same enantiomer with E-enone 2h. In the case of
alkyl substrates Z-4e, the flexible linear alkyl group does not
provide enough steric hindrance, so the s-cis conformation is still
favored in this situation and the resulting product has opposite
configuration with that provided by E-4e (Fig. 2).
16
17
Allyl
3o
87
84
96
94
Allyl
3p
3q
18
19
a
Et 1e
82
90
499c,d
Bu 1f 3r
99d
Unless otherwise noted, reactions were carried out with 1 (0.375 mmol,
1.5 eq) and 2 (0.25 mmol) in 2.5 mL toluene at 40 1C for 12 h. b The
enantiomeric excess was determined by HPLC analysis. c Absolute configu-
ration of 3q was determined to be S by X-ray crystallography and the rest
were assigned by analogy. d The reaction was performed at 60 1C.
In conclusion, dialkyl phosphine oxides were found as a class
of highly reactive nucleophiles in the catalytic asymmetric
phospha-Michael reaction with b,b-disubstituted a,b-unsaturated
carbonyl compounds. The products bearing tetrasubstituted
carbon stereocenters were obtained in high yields with excellent
enantioselectivities (up to 499% ee). A relatively wide range of
substrates scope was achieved in this process. Further investigations
of the reaction mechanism and applications of the phospha-
Michael adducts are ongoing.
We are grateful for the grants from the National Natural Science
Foundation of China (no. 90813012 and 20932003), the Key
National S&T Program ‘‘Major New Drug Development’’ of the
Ministry of Science and Technology (2012ZX09504001-003).
c
890 Chem. Commun., 2012, 48, 889–891
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Notes and references
1 For reviews on the synthesis of quaternary stereocenters, see:
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Fig. 1 X-Ray of 3q and proposed transition-state model.
Table 3 Scope of the b,b-disubstituted N-acylpyrroles
Entrya
Substrate
Product
Yield (%)
eeb (%)
499
96
1
2
3
4
4a
4b
4c
4d
88
91
96
93
94
94
5
6
4e
4e
90
95
98
À97
a
Unless otherwise noted, reactions were carried out with 1d (0.375 mmol,
1.5 equiv.) and 5 (0.25 mmol) in 2.5 mL toluene at 40 1C for 12 h. b The
enantiomeric excess was determined by HPLC analysis.
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9 Only a few number of successful examples were published
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ref. 3f, 3k, 4a, 4b, 5a, 5b and 6a.
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Chem., 2010, 75, 6756; (c) D. Zhao, D. Yang, Y.-J. Wang, Y. Wang,
L. Wang, L. Mao and R. Wang, Chem. Sci., 2011, 2, 1918.
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Chem. Soc., 2009, 131, 4572; (c) B. M. Trost, V. S. Chan and
D. Yamamoto, J. Am. Chem. Soc., 2010, 132, 5186; (d) B.-L. Wang,
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12 R. G. Pearson and J. Songstad, J. Am. Chem. Soc., 1967, 89, 1827.
13 CCDC 842933 contains the supplementary crystallographic data
for 3q.
Fig. 2 Different pathways of Z-substrates.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 889–891 891