Organocatalytic asymmetric Michael-type/wittig reaction of phosphorus ylides: Synthesis of chiral α-methylene-δ-ketoesters

Article abstract of DOI:10.1021/ol201483s

An asymmetric Michael-type reaction of phosphorus ylides and α,β-unsaturated ketones under the catalysis of a chiral ion pair catalyst has been described. The ion pair catalyst containing a chiral counteranion was prepared by simply mixing 9-amino-(9-deoxy)-epi-quinine with l-N-Boc-proline. The optically active α-methylene-δ-ketoesters could be obtained with good to excellent enantioselectivities (up to 95% ee) under mild reaction conditions.

Full text of DOI:10.1021/ol201483s

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4176–4179
Organocatalytic Asymmetric
Michael-Type/Wittig Reaction of
Phosphorus Ylides: Synthesis of Chiral
r-Methylene-δ-Ketoesters
Aijun Lin,† Junying Wang,† Haibin Mao,† Huiming Ge,‡ Renxiang Tan,‡
Chengjian Zhu,*,† and Yixiang Cheng*,†
School of Chemistry and Chemical Engineering, State Key Laboratory of Coordination
Chemistry, Nanjing University, Nanjing, 210093, China, and State Key Laboratory of
Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing,
210093, China
cjzhu@nju.edu.cn; yxcheng@nju.edu.cn
Received June 1, 2011
ABSTRACT
An asymmetric Michael-type reaction of phosphorus ylides and R,β-unsaturated ketones under the catalysis of a chiral ion pair catalyst has been
described. The ion pair catalyst containing a chiral counteranion was prepared by simply mixing 9-amino-(9-deoxy)-epi-quinine with L-N-Boc-
proline. The optically active R-methylene-δ-ketoesters could be obtained with good to excellent enantioselectivities (up to 95% ee) under mild
reaction conditions.
Since the pioneering work of MacMillan,1 the asym-
metric Michael-type reaction of R,β-unsaturated carbonyl
compounds under the catalysis of chiral amine through the
iminium-ion mediated pathway has been established as
one of the most typical and versatile methods of CÀC
bond-forming reaction, which is widely applied in organic
and medicinal chemistry.2 Chiral δ-ketoesters, a type of
useful synthetic intermediate, has been reported by
Jørgensen3 and Ley4 through the decarboxylation of the
Michael adducts of malonates and R,β-unsaturated ke-
tones. Although the reaction could be performed in a one-
pot decarboxylationÀtransesterification procedure, the
decarboxylation strategy is still tedious. In this commu-
nicationwewouldliketoreportthe development of a novel
(5) Wittig, G.; Geissler, G. Liebigs Ann. Chem. 1953, 580, 44.
(6) (a) Bestmann, H. J.; Schultz, H. Tetrahedron Lett. 1960, 4, 5. (b)
Bestmann, H. J.; Seng, F. Angew. Chem. 1962, 74, 154. (c) Asunskis, J.;
Shechter, H. J. Org. Chem. 1968, 33, 1164. (d) Von Strandtmann, M.;
Cohen, M. P.; Puchalski, C.; Shavel, J., Jr. J. Org. Chem. 1968, 33, 4306.
(e) Connor, D. T.; Von Strandtmann, M. J. Org. Chem. 1973, 38, 1047.
(f) Nesmeyanov, N. A.; Kharitonov, V. G.; Zhuzhlikova, S. T.; Petrovskii,
P. V.; Antipin, M. Yu.; Struchkov, Yu. T.; Reutov, O. A. Zh. Org. Khim.
1987, 23, 1577. (g) Aitken, R. A.; Al-Awadi, N. A.; Balkovich, M. E.;
† School of Chemistry and Chemical Engineering.
‡ School of Life Sciences.
(1) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2000, 122, 4243.
(2) (a) Lelais, G.; MacMillan, D. W. C. Aldrichimica Acta 2006, 39,
79. (b) Erkkila, A.; Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107,
5416. (c) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701. (d) Almasi, D.;
ꢀ
Alonso, D. A.; Najera, C. Tetrahedron: Asymmetry 2007, 18, 299. (e)
€
Enders, D.; Grondal, C.; Huttl, M. R. M. Angew. Chem., Int. Ed. 2007,
46, 1570.
€
Bestmann, H. J.; Clem, O.; Gibson, S.; Gross, A.; Kumar, A.; Roder, T.
Eur. J. Org. Chem. 2003, 840. (h) Sun, X.-L.; Tang, Y. Acc. Chem. Res.
2008, 41, 937. (i) Ye, L.-W.; Han, X.; Sun, X.-L.; Tang, Y. Tetrahedron
2008, 64, 8149. (j) Ye, L.-W.; Wang, S.-B.; Wang, Q.-G.; Sun, X.-L.; Tang,
Y.; Zhou, Y.-G. Chem. Commun. 2009, 3092. (k) Liu, W.-B.; He, H.; Dai,
L.-X.; You, S.-L. Chem.;Eur. J. 2010, 16, 7376.
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r
10.1021/ol201483s
Published on Web 07/14/2011
2011 American Chemical Society

and facile strategy to the enantioselective synthesis of
R-methylene-δ-ketoesters.
the chiral communication between the iminum ions and
the substrates by shielding one of the two enantiotopic
faces. And the stereochemical control could be effectively
induced by these chiral anions. This strategy has been
defined as asymmetric counterion-directed catalysis
(ACDC) by List.10b Additionally, 9-amino cinchona alka-
loids, directlyderived from natural cinchona alkaloids,11 in
combination with various acids, have been shown as
excellent iminium activators of simple ketones in asym-
metric conjugate addition reactions.12 Herein we show that
the combination of 9-amino-(9-deoxy)-epi-quinine and
L-N-Boc-proline resulted in an effective catalytic amine
salt for the enantioselective Michael-type reaction of phos-
phorus ylides and R,β-unsaturated ketones.
Initial examination was carried out by using the P-ylide
2aand trans-4-phenyl-3-buten-2-one3aasthesubstrates in
the presence of a series of chiral primary amine salt
catalysts in CH2Cl2 at À15 °C. Preliminary studies con-
firmed that AcOH salts of catalyst 1aÀ1d were able to
promote the reaction, and the expected P-ylide intermedi-
ate 4a could be isolated as a relatively stable compound.
After reaction with formaldehyde, the product 5a was
obtained in moderate yield with low enantioselectivity
(Table 1, entries 1À4). Notably, when 9-amino-(9-deoxy)-
epi-quinine 1e combined with AcOH was tested, 5a was
isolated with an obvious increased enantioselectivity
(Table 1, entry 5). When 1e together with TFA, p-nitro-
benzoic acid, or p-toluenesulfonic acid was tested, moder-
ate enantioselectivity was obtained (Table 1, entries 6À8).
Considering the natureof thecounteranion isanimportant
factor in the asymmetric induction, we thus decided to
introduce chiral acid to the catalytic system to improve the
enantioselectivity. To our delight, when 1e with L-N-Boc-
phenylglycine (A) was tested in the reaction, an increased
enantioselectivity was achieved (Table 1, entry 9). The best
enantioselectivity (80% ee) was observed when L-N-Boc-
proline (B) was used (Table 1, entry 10). A lower tempera-
ture (À30 °C) caused the loss of yields from 56% to 33%
without an obvious increased ee value (Table 1, entry 14).
Stabilized phosphorus ylides (P-ylides), which were ex-
tensively used in organic chemistry since the discovery of
the Wittig reaction,5 have previously been shown as good
nucleophiles in organic synthesis.6 However, the applica-
tion of phosphorus ylides in asymmetric synthesis is cur-
rentlylimited. In2008, Chenpresentedthefirst asymmetric
Mannich-type reaction of phosphorus ylides and aldi-
mines, followed by a Wittig reaction; the aza-MoritaÀ
BaylisÀHillman products could be obtained with excellent
enantioselectivities.7 Subsequently, Lee8 and Singh9 inde-
pendently reported the asymmetric Michael-type reaction
of phosphorus ylides and nitroolefin with good results.
Inspired by these successful examples with phosphorus
ylides as nucleophiles in the asymmetric addition reaction,
we are recently surprised to find that the phosphorus ylides
are also suitable nucleophilic species for the addition of
R,β-unsaturated ketones under the catalysis of chiral
amine salts. After proton transfer, a stabilized phosphorus
ylide intermediate could be obtained, which undergoes a
Wittig reaction with formaldehyde to give R-methylene-δ-
ketoesters in a novel reaction pathway (Scheme 1).
Scheme 1. A Novel Pathway to the Synthesis of R-Methylene-δ-
Ketoesters
Recently, the introduction of a chiral Brønsted acid to
the amine catalytic system has been proven as an impactful
catalytic system in asymmetric aminocatalysis.10 In these
catalytic systems, the yielded chiral anions could enhance
(11) Brunner, H.; Ngler, J. B.; Nuber, B. Tetrahedron: Asymmetry
1995, 6, 1699.
(12) For recent reviews on asymmetric primary amine catalysis, see:
(a) Peng, F.; Shao, Z. J. Mol. Catal. A: Chem. 2008, 285, 1. (b) Xu, L.-W.;
Lu, Y. Org. Biomol. Chem. 2008, 6, 2047. (c) Chen, Y.-C. Synlett. 2008,
1919. (d) Bartoli, G.; Melchiorre, P. Synlett 2008, 1759. (e) Xu, L.-W.;
Lu, Y. Chem. Commun. 2009, 1807. For selected excellent examples
about 9-amino cinchona alkaloids as iminium activators of simple
ketones, see: (f) Xie, J.-W.; Chen, W.; Li, R.; Zeng, M.; Du, W.; Yue,
L.; Chen, Y.-C.; Wu, Y.; Zhu, J.; Deng, J.-G. Angew. Chem., Int. Ed.
2007, 46, 389. (g) Chen, W.; Du, W.; Duan, Y.-Z.; Wu, Y.; Yang, S.-Y.;
Chen, Y.-C. Angew. Chem., Int. Ed. 2007, 46, 7667. (h) Zhou, J.;
Wakchaure, V.; Kraft, P.; List, B. Angew. Chem., Int. Ed. 2008, 47,
7656. (i) Lu, X.-J.; Deng, L. Angew. Chem., Int. Ed. 2008, 47, 7710. (j)
Reisinger, C. M.; Wang, X. -W.; List, B. Angew. Chem., Int. Ed. 2008, 47,
8112. (k) Singh, P. R.; Bartelso, K.; Wang, Y.; Su, H.; Lu, X.-J.; Deng, L.
J. Am. Chem. Soc. 2008, 130, 2422. (l) Wang, X.; Reisinger, C. M.; List,
B. J. Am. Chem. Soc. 2008, 130, 6070. (m) Lu, X.-J.; Liu, Y.; Sun, B.;
Cindric, B.; Deng, L. J. Am. Chem. Soc. 2008, 130, 8134. (n) Wu, L.-Y.;
Bencivenni, G.; Mancinelli, M.; Mazzanti, A.; Bartoli, G.; Melchiorre,
P. Angew. Chem., Int. Ed. 2009, 48, 7196. (o) Bencivenni, G.; Wu, L.-Y.;
Mazzanti, A.; Giannichi, B.; Pesciaioli, F.; Song, M.-P.; Bartoli, G.;
Melchiorre, P. Angew. Chem., Int. Ed. 2009, 48, 7200. (p) Paixao, M. W.;
Holub, N.; Vila, C.; Nielsen, M.; Jøgensen, K. A. Angew. Chem., Int. Ed.
2009, 48, 7338. (q) Qiao, Z.; Shafiq, Z.; Liu, L.; Yu, Z.-B.; Zheng, Q.-Y.;
Wang, D.; Chen, Y.-J. Angew. Chem., Int. Ed. 2010, 49, 7294.
(7) Zhang, Y.; Liu, Y.-K.; Kang, T.-R.; Hu, Z.-K.; Chen, Y.-C. J.
Am. Chem. Soc. 2008, 130, 2456.
(8) Hong, B.-C.; Jan, R.-H.; Tsai, C.-W.; Nimje, R. Y.; Liao, J.-H.;
Lee, G.-H. Org. Lett. 2009, 11, 5246.
(9) Allu, S.; Selvakumar, S.; Singh, V. K. Tetrahedron Lett. 2010, 51,
446.
(10) For recent reviews, see: (a) Piovesana, S.; Schietroma, D. M. S.;
Bella, M. Angew. Chem., Int. Ed. 2011, 50, 2. For selected examples, see:
(b) Mayer, S.; List, B. Angew. Chem., Int. Ed. 2006, 45, 4193. (c) Martin,
N. J. A.; List, B. J. Am. Chem. Soc. 2006, 128, 13368. (d) Zhou, J.; List, B.
J. Am. Chem. Soc. 2007, 129, 7498. (e) Ricci, P.; Carlone, A.; Bartoli, G.;
Bosco, M.; Sambri, L.; Melchiorre, P. Adv. Synth. Catal. 2008, 350, 49.
(f) Wang, X.; List, B. Angew. Chem., Int. Ed. 2008, 47, 1119. (g)
Pesciaioli, F.; De Vincentiis, F.; Galzerano, P.; Bencivenni, G.; Bartoli,
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Org. Lett., Vol. 13, No. 16, 2011
4177

The examination of solvent effects revealed that ClCH2-
CH2Cl was the best reaction media for this reaction, which
could facilitate the reaction to produce the corresponding
product in 64% yield with 82% ee (Table 1, entry 18).
Decreasing the catalyst loading to 10 and 5 mol % had a
negative impact on both the yields and the enantioselec-
tivities (Table 1, entries 19À20). Additionally, the optically
pure 4a was obtained upon recrystallization, the absolute
configuration was determined to be S by means of X-ray
crystallographic analysis (Figure 1),13 and the absolute
configuration of the corresponding product 5a could also
be determined to be S.
Table 1. Screening Studies of the Michael-Type Reaction Con-
ditions and Subsequent Synthesis of R-Methylene-δ-Ketoestera
yield
(%)b
ee
entry
cat.
additive
AcOH
solvent
(%)c
Figure 1. X-ray structure of enantiopure 4a. Thermal ellipsoids
are shown at 30% probability.
1
1a
1b
1c
1d
1e
1e
1e
1e
1e
1e
1e
1e
1e
1e
1e
1e
1e
1e
1e
1e
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
CH3CN
THF
41
35
39
45
55
42
50
38
51
56
47
40
67
33
42
trace
35
64
51
39
8
2
AcOH
15
21
18
63
57
61
55
76
80
75
78
71d
84e
61
n.df
49
82
75g
64h
3
AcOH
Having established the optimal reaction conditions, we
then examined a spectrum of P-ylide 2 and R,β-unsatu-
rated ketones 3 to explore the generality of this new
asymmetric successive Michael-type/Wittig reaction. The
reactions were conducted in 0.5 mL of ClCH2CH2Cl with
20 mol % of catalyst 1e and 40 mol % of L-N-Boc-proline
(B) atÀ15 °C for 84 h. The results are summarized in Table 2.
Based on entries 1À4 of Table 2, the enantioselectivities
were slightly dependent on the substituted ester groups of
the P-ylide 2. The electronic properties of the phenyl ring
of the R,β-unsaturated ketones did not influence the level
of the enantioselectivity markedly, and all these sub-
strates accomplished the reaction smoothly (Table 2,
entries 5À11). Moreover, when 2-thienyl-substituted ketone
was used as the substrate, the corresponding product 5l
was obtained in 55% yield with 88% ee (Table 2, entry 12).
β-Alkyl-substituted ketone was also tested; luckily, the
reaction was completed with 83% ee (Table 2, entry 13).
As is evident from entries 1À3 of Table 3, an exchange of
the methyl group of the ketone to an ethyl group or a
propyl group improved the enantioselectivity of the reac-
tion, with product 5n and 5o obtained with 92% ee and
94% ee, respectively. However, a further increase of the
steric bulk at the R3-position to an isopropyl group slowed
down the reaction and a very low conversion (<5%) was
4
AcOH
5
AcOH
6
TFA
7
p-NO2PhCOOH
8
TsOH
A
9
10
11
12
13
14
15
16
17
18
19
20
B
C
D
B
B
B
B
B
CHCl3
DCE
B
B
DCE
B
DCE
a The reaction was carried out with 0.20 mmol of 2a, 0.30 mmol of 3a,
and 20 mol % of catalyst 1 in combination with 40 mol % of additive
in 0.5 mL of solvent at À15 °C for 84 h. b Isolated yield for two steps.
c Ee values were determined by chiral HPLC analysis. d 0 °C reac-
tion temperature. À30 °C reaction temperature. f Not determined.
e
g 10 mol % of catalyst 1e was used. h 5 mol % of catalyst 1e was used.
observed. These results revealed that a longer chain ketone
could engender higher enantioselectivity. Then a series of
long chain ketones were synthesized and utilized in this
reaction; all of the corresponding products were obtained
with excellent enantioselectivities, and the ee values ranged
from 94% to 95% (Table 3, entries 4À11).
(13) CCDC 827398 (4a) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc. cam.ac.uk/
data_request/cif.
Based on the above results, we proposed a transition
state for the catalytic asymmetric Michael-type reaction.
4178
Org. Lett., Vol. 13, No. 16, 2011

Table 2. Asymmetric Synthesis of R-Methylene-δ-Ketoesters
Table 3. Asymmetric Synthesis of R-Methylene-δ-Ketoesters
via Successive Michael-Type/Wittig Reactiona
via Successive Michael-Type/Wittig Reactiona
2
(R1)
3
(R2)
yield
(%)b
ee
(%)c
2
(R1)
3
(R3)
yield
(%)b
ee
(%)c
entry
entry
1
Et
Ph
Ph
Ph
Ph
64 (5a)
67 (5b)
54 (5c)
60 (5d)
53 (5e)
61 (5f)
67 (5g)
58 (5h)
50 (5i)
48 (5j)
71 (5k)
55 (5l)
65 (5m)
82
78
73
81
80
78
81
81
82
80
72
88
83
1
Et
Me
64 (5a)
58 (5n)
54 (5o)
56 (5p)
49 (5q)
52 (5r)
47 (5s)
50 (5t)
62 (5u)
53 (5v)
46 (5w)
82
92
94
95
95
95
95
95
94
94
95
2
Me
i-Pr
Bn
Et
2
Et
Et
3
3
Et
n-Pr
4
4
Et
n-Bu
n-Pen
n-Hex
n-Hep
n-Oct
n-Pen
n-Pen
n-Pen
5
4-FPh
5
Et
6
Et
4-ClPh
3-ClPh
4-BrPh
4-MePh
4-MeOPh
4-NO2Ph
2-thienyl
n-Bu
6
Et
7
Et
7
Et
8
Et
8
Et
9
Et
9
Me
i-Pr
Bn
10
11
12
13
Et
10
11
Et
Et
a The reaction was carried out with 0.20 mmol of 2, 0.30 mmol of 3,
and 20 mol % of catalyst 1e in combination with 40 mol % of B in 0.5 mL
of ClCH2CH2Cl at À15 °C for 84 h. b Isolated yield for two steps. c Ee
values were determined by chiral HPLC analysis.
Bn
a The reaction was carried out with 0.20 mmol of 2, 0.30 mmol of 3,
and 20 mol % of catalyst 1e in combination with 40 mol % of B in 0.5 mL
of ClCH2CH2Cl at À15 °C for 84 h. b Isolated yield for two steps. c Ee
values were determined by chiral HPLC analysis.
In summary, we have provided an organocatalytic Mi-
chael-type addition of phosphorus ylides and R,β-unsatu-
rated ketones using a chiral ion pair catalyst. And the
catalyst was easily prepared by mixing 9-amino-(9-deoxy)-
epi-quinine with L-N-Boc-proline. The reaction proceeded
with a great diversity of R,β-unsaturated ketones with
good to excellent enantioselectivities (up to 95% ee).
Following a Wittig reaction with formaldehyde, the scope
of the reaction was demonstrated by the synthesis of chiral
R-methylene-δ-ketoesters. Further exploration of using
phosphorus ylides as the nucleophiles in asymmetric reac-
tions is now in progress in our laboratory.
Acknowledgment. We gratefully acknowledge the Na-
tional Natural Science Foundation of China (20832001,
20972065, 21074054) and the National Basic Research
Program of China (2007CB925103, 2010CB923303) for
their financial support.
Figure 2. Proposed transition state for the Michael-type reaction
of phosphorus ylides and R,β-unsaturated ketones.
The interaction between ketone and amine would adopt
a trans conformation. The phosphorus ylide is much
more accessible to attack the active iminium from
the Si face, affording the corresponding product as
S (Figure 2).
Supporting Information Available. Experimental pro-
cedures, structural proofs, NMR spectra, and HPLC
chromatograms of the products. This material is available
free of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 16, 2011
4179