Asymmetric Michael addition of α-hydroxyketones to nitroolefins catalyzed by chiral diamine

Article abstract of DOI:10.1021/ol0348755

(Matrix presented) The regio-, stereo-, and enantioselective direct Michael addition of α-hydroxyketones to β-arylnitroolefins catalyzed by N-iPr-2,2′-bipyrrolidine is described. The formation of an internal hydrogen bond between the OH group of α-hydoxya

Full text of DOI:10.1021/ol0348755

ORGANIC
LETTERS
2003
Vol. 5, No. 14
2559-2561
Asymmetric Michael Addition of
r-Hydroxyketones to Nitroolefins
Catalyzed by Chiral Diamine
Olivier Andrey, Alexandre Alexakis,* and Ge´rald Bernardinelli
Chimie Organique, Sciences II, UniVersity of GeneVa, Quai Ernest Ansermet,
CH-1211, GeneVa, Switzerland
alexandre.alexakis@chiorg.unige.ch
Received May 20, 2003
ABSTRACT
The regio-, stereo-, and enantioselective direct Michael addition of r-hydroxyketones to â-arylnitroolefins catalyzed by N-iPr-2,2′-bipyrrolidine
is described. The formation of an internal hydrogen bond between the OH group of r-hydoxyacetone and the tertiary nitrogen of the catalyst
leads to the formation of a rigid cis enamine intermediate that explains the inversion of the expected diastereoselectivity and the very high
ee’s.
The development of nonmetallic asymmetric catalysis has
received much attention since its rediscovery in the beginning
of the 21st century.1 Indeed, following the famous asym-
metric annulation catalyzed by L-proline in the 1970s,2
reported by Hajos et al. and Wiechert et al., almost nothing
new was published. Only recently have many examples of
reactions catalyzed by L-proline been reported, such as aldol
reactions, Mannich reactions, conjugate additions, or R-ami-
nations.3 At the same time, new amines were developed as
catalysts and were also used in aldol reactions,4 Mannich
reactions,5 and conjugate additions.6 All of these reactions
are known under the neologism of organocatalysis.
(g) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000, 122,
2395. (h) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc.
2000, 122, 2395. Mannich reaction: (i) Cordova, A.; Barbas III, C. F.
Tetrahedron Lett. 2003, 44, 1923. (j) Watanabe, S.; Cordova, A.; Tanaka,
F.; Barbas, C. F., III. Org. Lett. 2002, 4, 4519. (k) Cordova, A.; Watanabe,
S.-i.; Tanaka, F.; Notz, W.; Barbas, C. F., III. J. Am. Chem. Soc. 2002,
124, 1866. (l) Notz, W.; Sakthivel, K.; Bui, T.; Zhong, G.; Barbas, C. F.,
III. Tetrahedron Lett. 2001, 42, 199. Conjugate addition: (m) Enders, D.;
Seki, A. Synlett 2002, 26. (n) List, B.; Pojarliev, P.; Martin, H. J. Org.
Lett. 2001, 3, 2423. R-Amination: (o) List, B. J. Am. Chem. Soc. 2002,
124, 5656. (p) Kumaragurubaran, N.; Juhl, K.; Zhuang, W.; Bogevig, A.;
Jorgensen, K. A. J. Am. Chem. Soc. 2002, 124, 6254. (q) Bogevig, A.;
Juhl, K.; Kumaragurubaran, N.; Zhuang, W.; Jorgensen, K. A. Angew.
Chem., Int. Ed. 2002, 41, 1790.
(1) For recent reviews on this subject, see: (a) Jarvo, E. R.; Miller, S.
J. Tetrahedron 2002, 58, 2481. (b) List, B. Tetrahedron 2002, 58, 5573.
(c) List, B. Synlett 2001, 1675. (d) Dalko, P. I.; Moisan, L. Angew. Chem.,
Int. Ed. 2001, 40, 3726.
(2) (a) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. Engl.
1971, 83, 492. (b) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39,
1615.
(4) Saito, S.; Nakadai, M.; Yamamoto, H. Synlett 2001, 8, 1245.
(5) Cordova, A.; Barbas, C. F., III. Tetrahedron Lett. 2002, 43, 7749.
(6) (a) Brown, S. P.; Goodwin, N. C.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2003, 125, 1192. (b) Halland, N.; Aburel, P. S.; Jorgensen, K. A.
Angew. Chem., Int. Ed. 2003, 42, 661. (c) Paras, N. A.; MacMillan, D. W.
C. J. Am. Chem. Soc. 2002, 124, 7894. (d) Austin, J. F.; MacMillan, D. W.
C. J. Am. Chem. Soc. 2002, 124, 1172. (e) Halland, N.; Hazell, R. G.;
Jorgensen, K. A. J. Org. Chem. 2002, 67, 8331. (f) Paras, N. A.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2001, 123, 4370. (g) Betancort, J. M.; Barbas,
C. F., III. Org. Lett. 2001, 3, 3737. (h) Betancort, J. M.; Sakthivel, K.;
Thayumanavan, R.; Barbas, C. F., III. Tetrahedron Lett. 2001, 42, 4441.
(3) For recent examples of L-proline-catalyzed reactions, see the fol-
lowing. Aldol reaction: (a) Northrup, A. B.; MacMilan, D. W. C. J. Am.
Chem. Soc. 2002, 124, 6798. (b) Co´rdova, A.; Notz, W.; Barbas, C. F., III.
J. Org. Chem. 2002, 67, 301. (c) Chowdari, N. S.; Ramachary, D. B.;
Cordova, A.; Barbas III, C. F. Tetrahedron Lett. 2002, 43, 9591. (d)
Cordova, A.; Notz, W.; Barbas III, C. F. Chem. Commun. 2002, 3024. (e)
Bogevig, A.; Kumaragurubaran, N.; Anker Jorgensen, K. Chem. Commun.
2002, 620. (f) List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573.
10.1021/ol0348755 CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/10/2003

We7 and others,3m,n,6f have recently reported the organo-
catalyzed conjugate addition of aldehydes and ketones to
nitrostyrene. It was shown that L-proline was not very
efficient (lower yields and ee’s) compared to diamines. One
of the problems we met for nonsymmetrical ketones was the
regioselectivity. Therefore, we decided to test R-alkoxycar-
bonyl compounds to see if the regioselectivity of the reaction
could be controlled. Indeed, it is commonly accepted that,
in the catalytic cycle, an iminium is formed before being
deprotonated to the reactive nucleophilic enamine. The
difference of acidity between the R and R′ protons leads
exclusively to the enol/enamine intermediate (Scheme 1).
Table 1. Asymmetric Addition of R-alkoxycarbonyl
Compounds to Nitrostyrene, Catalyzed by Diamine iPBP
reaction
R2 solvent conditions anti/syn
dra
yieldb eec
entry
R1
(%)
(%)
1
2
3
4
5
6
7
8
Me
Me
n-Pr
Me
Me
Me
Me
Me
Me
Me
Me CHCl3
rt, 2 days
rt, 7 days
60 °C, 7 d
17:83
83:17
92:8
82:18
70:30
60:40
75:25
68:32
75
79
21
68
60
37
53
48
0d
69
H
H
H
H
H
H
H
H
H
CHCl3
CHCl3
CH2Cl2 rt, 7 days
Et2O
THF
MeOH
iPrOH
DMF
97.6
98.4
98.3
81
73
93
Scheme 1. Proposed Mechanism for Diamine-Catalyzed
Michael Addition
rt, 7 days
rt, 7 days
rt, 2 days
rt, 4 days
rt, 7 days
rt, 4 days
75
9
10e
MeOH
30:70
67
11
a Determined by 1H NMR or SFC of the crude product. b Isolated yield
after column chromatography. c Determined by chiral GC or SFC of the
purified product (major diastereomer). d Decomposition of the starting
marterial. e With L-proline as chiral catalyst.
The use of R-alkoxycarbonyls has already been described
in aldol reactions8 and Mannich reactions,9 catalyzed by
L-proline, with very high stereoselectivities and regioselec-
tivities. In this communication, we report the first asymmetric
organocatalyzed conjugate addition of R-hydroxyketones to
nitroolefins.
Screening of different solvents has shown that chlorinated
solvents, CHCl3 (entry 2) and CH2Cl2 (entry 4), gave higher
yields and stereoselectivities. We have then tested 1-hydroxy-
pentan-2-one, which gave the adduct after 7 days at 60 °C
with a very high stereoselectivity but low yield (entry 3),
probably because of the thermal instability of the adduct.
We explain the inversion of diastereoselectivity, between
the pyrrolidine catalysis and the chiral bipyrrolidine deriva-
tives iPBP, by the presence of a second nitrogen that fixes
the conformation via a hydrogen bond to give the cis enamine
instead of the trans one. Thus, the high enantioselectivities
obtained are due to the resulting rigid reactive intermediate
(Scheme 1). The relative approach of the reactants should
follow Seebach’s model, who explained the selectivity by
an acyclic synclinal model.10
In a second step, the addition of R-hydroxyacetone to
different â-arylnitroolefins 1-10a was tested, and the results
are summarized in Table 2. All reactions were carried in
chloroform with 15% catalyst and 10 equiv of ketone for a
duration of 7 days.
We have observed only little differences in enantioselec-
tivity between the adducts 1b-10b. Generally speaking,
electron-withdrawing groups on the aryl moiety gave slightly
higher yields and stereoselectivities. Unfortunately, nonaro-
matic nitroolefins, such as â-cyclohexylnitroethene or â-(n-
butyl)-nitroethene, did not react with R-hydroxyacetone. This
was presumably due to the faster addition of the catalyst to
nitroolefin than to ketone.
We have first performed the racemic version by using
pyrrolidine as catalyst for the addition of R-methoxyacetone
and R-hydroxyacetone to nitrostyrene. The reaction is fully
regioselective, and the racemic adduct was obtained in both
cases in favor of the syn isomer as predicted. The asymmetric
version was carried out with our previously reported diamine,
(S,S)-N-iPr-2,2′-bipyrrolidine (iPBP);7 The results are sum-
marized in Table 1. The addition of R-methoxyacetone in
chloroform provided, as expected, the desired product (entry
1) with a good selectivity (69% ee, anti/syn 17:83), but
surprisingly, the addition of R-hydroxyacetone (entry 2),
under the same conditions as above, led to the opposite
diastereomer (anti/syn 83:17) with a very high enantiocontrol
(98% ee). This result, with diamine iPBP, was much better
than the one obtained in a preliminary attempt using L-proline
as chiral catalyst. L-Proline, one of the most widely used
organocatalysts, gave after 4 days, in methanol, the addition
product of R-hydroxyacetone to nitrostyrene, with a very poor
stereo- and enantiocontrol (67% yield, 11% ee (syn), anti/
syn 30:70). It is interesting to note that the major diastere-
omer is the syn adduct (entry 10).
(7) Alexakis, A.; Andrey, O. Org. Lett. 2002, 4, 3611.
(8) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III. J. Am. Chem.
Soc. 2001, 123, 5260
(9) (a) Cordova, A.; Notz, W.; Zhong, G.; Betancort, J. M.; Barbas, C.
F., III. J. Am. Chem. Soc. 2002, 124, 1842. (b) List, B.; Pojarliev, P.; Biller,
W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827. (c) List, B. J. Am.
Chem. Soc. 2000, 122, 9336.
(10) (a) Blarer, S. J.; Seebach, D. Chem. Ber. 1983, 116, 3086. (b) Ha¨ner,
R.; Laube, T.; Seebach, D. Chimia 1984, 38, 255. (c) Seebach, D.; Beck,
A. K.; Golinski, J.; Hay, J. N.; Laube, T. HelV. Chim. Acta 1985, 68, 162.
(d) Seebach, D.; Golinski, J. HelV. Chim. Acta 1981, 64, 1413.
2560
Org. Lett., Vol. 5, No. 14, 2003

Table 2. Asymmetric Addition of R-Hydroxyacetone to
Nitroolefins, Catalyzed by Diamine iPBP, in Chloroform
dra
yieldb
(%)
eec
entry/product
Ar
anti/syn
(%)
1
2
3
4
5
6
7
8
Ph
4-MePh
4-MeOPh
4-Cl-Ph
2-CF3Ph
2,6-Cl2Ph
3,4-Cl2Ph
2,4-Cl2Ph
1-naphthyl
2-thienyl
83:17
84:16
81:19
87:13
95:5
84:16
88:12
91:9
79
68
65
81
84
83
66
85
68
66
97.6
97.6
97.3
97.8
98.5
98.1
98.1
98.6
98.3
96.3
Figure 1. Ortep view of the X-ray crystal structure of 5c. Ellipsoids
are represented with 40% probability.
may be considered that the configuration of the others
adducts 1b-10b is the same.
In summary, we have demonstrated that L-proline is not a
universal oganocatalyst. For addition reactions to nitroolefins,
chiral diamines seem to be more selective. This is particularly
the case for the addition of R-hydroxyketones, which allow,
through a rigid transition state, an anti selectivity, with a
very high enantioselectivity.
9
10
78:22
78:22
a Determined by 1H NMR or SFC of the crude product. b Isolated yield
after column chromatography. c Determined by chiral SFC of the purified
product.
Acknowledgment. We thank the Swiss National Science
Foundation (grant 20-61891-00) for financial support.
The relative configuration of the adduct 5b was determined
by X-ray diffraction11 of its Mosher ester 5c (Figure 1). The
absolute configuration of center C2′ (R) being known, we
deduced the absolute configuration of adduct 5b (R,R). It
Supporting Information Available: Experimental pro-
cedures, 1H and 13C spectra and chiral separations for
compound 1b-10b; tables of crystal data, atomic coordi-
nates, bond lengths and angles, anisotropic displacements
parameters for 5c. This material is available free of charge
via the Internet at http://pubs.acs.org.
(11) X-ray data for 5c were collected at 200 K on a Stoe IPDS
diffractometer with Mo KR radiation. C22H19NO6F6, M ) 507.4; ortho-
rhombic, P212121, Z ) 4, a ) 9.8059(4), b ) 11.3493(7), c ) 20.3434(11)
Å, V ) 22264.0(2) Å3, R ) 0.030, ωR ) 0.031 (See Supporting Information
for further details).
OL0348755
Org. Lett., Vol. 5, No. 14, 2003
2561