Enantioselective organocatalytic phospha-Michael reaction of α,β-unsaturated ketones

Article abstract of DOI:10.1039/c0cc00094a

Enantioselective organocatalytic phospha-Michael reaction of α,β-unsaturated ketones and diaryl phosphine oxides has been developed for the first time employing multifunctional organocatalysts. Optically active products bearing quaternary chiral carbon st

Full text of DOI:10.1039/c0cc00094a

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COMMUNICATION
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Enantioselective organocatalytic phospha-Michael reaction
of a,b-unsaturated ketonesw
Shigang Wen, Pengfei Li, Haibo Wu, Feng Yu, Xinmiao Liang* and Jinxing Ye*
Received 24th February 2010, Accepted 7th May 2010
First published as an Advance Article on the web 25th May 2010
DOI: 10.1039/c0cc00094a
Enantioselective organocatalytic phospha-Michael reaction of
a,b-unsaturated ketones and diaryl phosphine oxides has been
developed for the first time employing multifunctional organo-
catalysts. Optically active products bearing quaternary chiral
carbon stereocenters were obtained in high yields with good to
excellent enantioselectivities (up to 98% ee).
quaternary carbon center using simple b,b-disubstituted
a,b-unsaturated ketones and dirayl phosphine oxides.
Over the past decade, chiral phosphines have been used as
powerful ligands for metal catalyzed enantioselective trans-
formations, and have achieved enormous progress in the
history of asymmetric catalysis.1 Also, they are recognized as
organocatalysts in organic reactions.2 Chiral phosphines are
traditionally obtained by standard resolution of racemic
materials.3 Recently, the catalytic asymmetric 1,4-addition of
trivalent phosphine compounds (R2PH) to electron-deficient
olefins, has provided straightforward access to useful chiral
phosphine compounds with different functional groups.4–6
Further development of catalytic asymmetric methods to
access diverse chemical functionalities, therefore, is still highly
desirable. The direct addition of P(O)–H bonds of dialkyl or
diaryl substituted phosphine oxides (R2P(O)H) to activated
alkenes is one of the most convenient routes to the stable
precursors of phosphine compounds. However, there are only
a few catalytic enantioselective methods available to access
this transformation. Among these methods, the most direct
approach is the asymmetric addition of phosphine oxides to
nitroolefins catalyzed by chiral guanidine for synthesis of
b-aminophosphine derivatives.7 To the best of our knowledge,
the asymmetric Michael reaction of phosphine oxides and
enones has not been investigated in the literature,8 in which
more challenging molecular complexity with chiral quaternary
carbon centers can be created.9
First, the Michael addition of cyclohex-2-enone and diphenyl-
phosphine oxide was examined using 1 (prepared from (1R,2R)-
1,2-diaminocyclohexane and 9-amino (9-deoxy) epiquinine) as a
catalyst, and the representative results are presented in Table 1.
The Michael addition proceeded with low enantioselectivity of
33% in THF solvent. Studies of the effect of the solvent showed
that CH2Cl2 was suitable for both conversion (76%, entry 8)
and enantioselectivity (90% ee). Other primary amine-thiourea
catalysts (2, 4, 5) with different chiral elemental assembly also
afforded moderate to good ee values (60–71%, entries 9, 11-12).
If the primary amine in 1 was substituted with two methyl groups
(catalyst 3), the conversion and enantioselectivity of the reaction
dramatically decreased to 22% and 15%, respectively. It
indicates that the primary amine group plays a key role in the
catalytic process (entry 10). The stereochemical outcome of the
Michael product remained when the cinchona alkaloid scaffold
of organocatalysts was changed to its pseudo enantiomer. As
(1R,2R)-1,2-diaminocyclohexane was switched to its enantiomer
(1 vs. 6), the stereochemical outcome of the Michael product was
reversed (entry 13). Therefore, it could be concluded that the
stereochemistry was dictated by the chiral 1,2-diaminocyclohexane
scaffold. And this also could explain the fact that low
enantioselectivity was obtained when the primary amine was
blocked. When 9-amino (9-deoxy) epiquinine (7) was used as
the catalyst, only 30% of conversion and 36% ee value were
afforded (entry 14). Therefore, the existence of a thiourea
group is also necessary for the catalytic process and stereo-
chemical control. The Michael addition proceeded well in the
presence of 8, a pseudo enantiomer of 1, and produced an
opposite stereochemical outcome (entry 16).
In this context, we have recently reported that a well-
designed multifunctional organocatalyst was
a valuable
platform for the development of enantioselective Michael
addition of a,b-unsaturated ketones.10 Based on these results,
we further expand this chemistry to achieve the first enantio-
selective organocatalytic Michael addition of pentavalent
diaryl phosphine oxides to a,b-unsaturated ketones. This
new approach of asymmetric conjugate addition also allows
the construction of phosphino compounds with chiral
Engineering Research Centre of Pharmaceutical Process Chemistry,
Ministry of Education, School of Pharmacy, East China University of
Science and Technology, 130 Meilong Road, Shanghai 200237, China.
E-mail: yejx@ecust.edu.cn; liangxm@ecust.edu.cn
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization of the Michael addition products.
CCDC 767563 & 767564. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c0cc00094a
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Table 1 Enantioselective organocatalytic phospha-Michael reaction
of cyclohexanone with diphenylphosphine oxidea
Table 2 Enantioselective organocatalytic phospha-Michael reaction
of various a, b-unsaturated ketones catalyzed by 1
Entry
Cat.
Solvent
Conv.(%)b
ee(%)c
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1
1
2
3
4
5
6
7
1
8
THF
80
79
76
82
81
76
72
76
65
22
23
49
46
30
98
90e
33
23
70
37
26
56
80
90
71
15
64
60
EtOAc
Toluene
Et2O
Dioxane
MeCN
CHCl3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
9
Entry Enone
P-Nu Adduct Yielda (%) eeb (%)
10
11
12
13
14
15d
16d
1
2
3
9a, R=H
14a
14a
14a
14a
14a
14a
14a
14a
15aa
15ba
15ca
15da
15ea
15fa
15ga
15ha
15ia
16
17a
18
19ab
19bb
19ib
17b
94
96
95
87
85
88
94
82
85
90
95
87
86
84
92
90
90
97
94
92
90
98
94
94
97
94
92
92
90
96
98
90
91
94
94
98
92
85
94
84
9b, R=Me
9c, R=Et
9d, R=Pr
ꢁ10
4c
5c
6c
7c
8
ꢁ36
90
9e, R=Bu
ꢁ90
9f, R = i-Bu
9g, R=Pentyl
9h, R=C2H4Ph
9i, R =cyclohexyl 14a
10
11
12
9a
9b
9i
11
a
Unless otherwise noted, all reactions were carried out using 0.1 mmol
of 1 (10 mol %), 1.0 mmol of 14a, and 3.0 mmol of 9a (3.0 equiv) in
9c
10
11
12
13
14
15c
16
17
18
19
20
b
2.0 mL of indicated solvent at room temperature. Conversion was
c
determined by GC. Enantiomeric excess was determined by chiral
14a
14a
14a
14b
14b
14b
14b
14a
14a
14a
14a
d
e
HPLC analysis (see ESIw for details). For 48 h. Isolated yield.
The generality of the methodology is shown in Table 2
under optimized conditions. The reactions between cyclic
enones and phosphine oxide nucleophiles are very successful
and the substituents on cyclohex-2-enone hardly affect the
yields and enantioselectivities of the Michael addition.
Cyclohex-2-enone reacted with 14a quite smoothly to form
the product in 94% isolated yield with 90% ee (entry 1). It
should be noted that 85–96% isolated yields with excellent
enantioselectivities (90–98%) were obtained in the reaction of
diphenylphosphine oxide and a variety of 3-substituted
cyclohex-2-enones (9b–i, 10). The reaction constructs phosphine
substituted quaternary stereocenters (entries 2–10), which is an
important yet challenging task in asymmetric synthesis.8
Especially, the reaction of 3-methylcyclohex-2-enone afforded
the desired adduct in up to 96% isolated yield with 98% ee
(entry 2). For sterically hindered 10, 90% isolated yield and up
to 96% ee were obtained (entry 10). The phospha-Michael
addition of 4-disubstituted cyclohex-2-enone (11) also
proceeded in excellent isolated yield and asymmetric induction
(entry 11). The addition of cyclohept-2-enone was further
investigated and 87% isolated yield and 90% ee were obtained
(entry 12). It is noteworthy that the sterically hindered
nucleophile 14b is also successfully used in this type of
Michael addition and 1,4-adducts were formed in 84–92%
isolated yields with 91–98% ee values (entries 13–16).
13a, R = 4-NO2
13b, R = 4-MeO
13c, R = 4-Br
13d, R = 3-Me
20aa
20ba
20ca
20da
a
b
Isolated yield of pure adducts. Enantiomeric excess was determined
c
by chiral HPLC. Reaction performed at 30 1C temperature with
20 mol% catalyst loading for the given time (see ESIw for details).
electron-donating substituents (entries 18, 21) can be introduced
into the aromatic ring without dramatic effect on the yield or
enantioselectivity. In contrast, the enantioselectivities of
less sterically hindered acyclic alkyl enones decreased.11
Unfortunately, no product was observed in the reaction of
cyclohex-2-enone and 4,40-dibromodiphenylphosphine oxide.
On the basis of the absolute configuration of the chiral
Michael products 15ba and 20ca from X-ray crystal structure
analysis (Scheme 1), a plausible catalytic mechanism by
concerted activation was proposed (Scheme 2).z The sense of
the enantioselectivity is dictated by the chiral trans-1,2-diamino-
cyclohexane unit, but the level of the stereoselection is
determined by the presence of a match rather than a mismatch
chiral 9-amino (9-deoxy) cinchona alkaloid unit.
In summary, we have developed a highly efficient and
enantioselective Michael addition of a,b-unsaturated ketones
with diaryl phosphine oxides using a multifunctional catalyst.
Optically active products bearing a quaternary chiral carbon
stereocenter were obtained in high yields with good to
excellent enantioselectivities (up to 98% ee). Current studies
in our laboratories aim at further expanding the scope and
application of this chemistry.
Further exploration found that the catalytic Michael additions
of a series of aromatic enones took place quite successfully to
form the products in 90–97% isolated yields (entries 17–20).
Although the asymmetric induction of aromatic enones was
slightly lower than that of cyclic enones, good to excellent
enantioselectivities (84–94%) were obtained. It should be
noted that electron-withdrawing (entries 17, 19 and 20) and
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Crystal structure determination of compound 15ba: C19H21O2P,
M = 312.33; a block crystal (0.56 ꢂ 0.52 ꢂ 0.44 mm), T = 296(2),
l(Mo-Ka) 0.71073 A, Orthorhombic, space group: P212121,
=
a = 6.3328(2) A, b = 9.3463(3) A, c = 28.2033(10) A, V =
1669.30(10) A3, 19388 total reflections, 2953 unique, Rint = 0.0257,
R1 = 0.0302 (I > 2s), wR2 = 0.0775. Flack parameter: 0.03(8).
Crystal structure determination of compound 20ca: C22H20BrO2P,
M = 427.26; a block crystal (0.10 ꢂ 0.05 ꢂ 0.05 mm), T = 273(2),
l(Mo-Ka) = 0.71073 A, Monoclinic, space group: C2, a = 19.698(4)
A, b = 5.7772(13) A, c = 17.469(4) A, V = 1983.8(8) A3, 3306 total
reflections, 1965 unique, Rint = 0.0343, R1 = 0.0427 (I > 2s),
wR2 = 0.0860, Flack parameter: 0.05(2).
Scheme 1 X-ray crystal structures of 15ba and 20ca.
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4 For a review about phospha-Michael additions, see: D. Enders,
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2006, 29.
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Scheme 2 Plausible catalytic mechanism by concerted activation.
We are grateful for the financial support from the National
Natural Science Foundation of China (20902018), the
Shanghai Pujiang Program (08PJ1403300), the Fundamental
Research Funds for the Central Universities and 111 Project
(B07023).
Notes and references
z General procedure for asymmetric Michael addition: To a solution
of a,b-unsaturated ketone (3.0 mmol) in DCM (2.0 mL) was added
diphenylphosphine oxide (1.0 mmol), catalyst (0.10 mmol). The
reaction mixture was stirred at given temperature. After completion
monitored by TLC, the product was purified by silica gel chromato-
graphy to yield the desired addition product. The enantiomeric excess
of the product was determined by HPLC analysis on chiral column.
10 (a) P. Li, Y. Wang, X. Liang and J. Ye, Chem. Commun., 2008,
3302; (b) P. Li, S. Wen, F. Yu, Q. Liu, W. Li. Y. Wang, X. Liang
and J. Ye, Org. Lett., 2009, 11, 753.
11 Pent-3-en-2-one (92% yield, 70% ee), oct-3-en-2-one (70% yield,
67% ee).
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This journal is The Royal Society of Chemistry 2010
4808 | Chem. Commun., 2010, 46, 4806–4808