Enantioselective conjugate addition of oximes to trisubstituted β-Nitroacrylates: An organocatalytic approach to β2,2-amino acid derivatives

Article abstract of DOI:10.1021/ol102580n

A highly enantioselective organocatalytic intermolecular conjugate addition of oximes to β-nitroacrylates has been developed. The highly functionalized adducts obtained are valuable precursors for asymmetric synthesis, as demonstrated by the synthesis of

Full text of DOI:10.1021/ol102580n

ORGANIC
LETTERS
2010
Vol. 12, No. 24
5636-5639
Enantioselective Conjugate Addition of
Oximes to Trisubstituted
ꢀ-Nitroacrylates: An Organocatalytic
Approach to ꢀ2,2-Amino Acid Derivatives
Fu-Gen Zhang, Qing-Qing Yang, Jun Xuan, Hai-Hua Lu, Shu-Wen Duan,
Jia-Rong Chen,* and Wen-Jing Xiao*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College
of Chemistry, Central China Normal UniVersity, 152 Luoyu Road, Wuhan,
Hubei 430079, China
wxiao@mail.ccnu.edu.cn; jiarongchen2003@yahoo.com.cn
Received September 30, 2010
ABSTRACT
A highly enantioselective organocatalytic intermolecular conjugate addition of oximes to ꢀ-nitroacrylates has been developed. The highly
functionalized adducts obtained are valuable precursors for asymmetric synthesis, as demonstrated by the synthesis of ꢀ2,2-amino acids and
oxazolidin-2-ones.
One focal objective of contemporary organic synthesis is to
develop catalytic asymmetric processes for the efficient
formation of carbon-carbon and carbon-heteroatom bonds.1
In this regard, the conjugate addition of O-nucleophiles to
electron-deficient olefins has proven to be one of the most
important but challenging methods for forming a carbon-
oxygen bond, which is frequently encountered in biologically
active natural products and pharmaceuticals.2 However, the
relative low reactivity of the O-nucleophiles and reaction
reversibility have hampered the development of asymmetric
variants of this reaction.3 To our knowledge, there are only
a few examples of highly enantioselective oxo-conjugate
addition reactions documented to date.4
With the use of a chiral catalyst (either metallic or organic),
the intramolecular conjugate addition becomes a powerful
tool to construct carbon-heteroatom bonds, using a variety
of heteroatom-based nucleophiles (S, O, P, N, etc.) and
electron-deficient alkenes.5 Surprisingly however, the analo-
gous intermolecular variant of heteroatom-based nucleophiles
to ꢀ,ꢀ-disubstituted R,ꢀ-unsaturated systems has not been
(1) (a) Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; ComprehensiVe
Asymmetric Catalysis; Springer: Berlin, 1999; Vols. I-III. (b) Berkessel,
H., Gro¨ger, H., Eds. Asymmetric Organocatalysis; Wiley-VCH: Weinheim,
2005. (c) MacMillan, D. W. C. Nature 2008, 455, 304. (d) Adair, G.;
Mukherjee, S.; List, B. Aldrichim. Acta 2008, 41, 31.
(3) For a recent review, see: (a) Nising, C. F.; Bra¨se, S. Chem. Soc.
ReV. 2008, 37, 1218. For a phosphine-catalyzed conjugate addition of water
and alcohols to variety of activated olefins, see: (b) Stewart, I. C.; Bergman,
R. G.; Toste, F. D. J. Am. Chem. Soc. 2003, 125, 8696. For a base-promoted
addition of alcohols to enones, see: (c) Kisanga, P. B.; Ilankumaran, P.;
Fetterly, B. M.; Verkade, J. G. J. Org. Chem. 2002, 67, 3555.
(2) For reviews on conjugate additions, see: (a) Perlmutter, P. Conjugate
Addition Reactions in Organic Synthesis; Pergamon Press: Oxford, U. K.,
1992. (b) Jung, M. E. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, U. K., 1991.
10.1021/ol102580n  2010 American Chemical Society
Published on Web 11/16/2010

extensively explored.4n,6 This presents an opportunity to
develop a highly desirable stereoselective system, that in
principle would provide an alternative synthetic technique
to the corresponding Aldol or Mannich-type reaction pro-
tocols.
As a continuing effort to develop solutions to complex
synthetic challenges, we herein describe a new approach to
the construction of a tertiary alcohol7 unit through organo-
catalytic intermolecular conjugate addition of oximes to
ꢀ-nitro-acrylates.8 This research describes the formation of
optically active R-oxylated ꢀ-nitro esters (15 examples,
91-98% ee), which are useful building blocks6b,9 for the
synthesis of ꢀ2,2-amino acids and oxazolidin-2-ones.
Pioneered by Jacobsen and co-workers4b in the Al(III)-
catalyzed highly enantioselective conjugate addition of
oximes to R,ꢀ-unsaturated imides, and later in the unprec-
edented organocatalytic hydroxylation of enals and nitroalk-
enes by Jørgensen and co-workers,4e,f oximes proved to be
a highly valuable class of “soft” oxygen nucleophiles. Due
to the planar character of an oxime which has minimal steric
hindrance, which we believe to be a key prerequisite for
successful conjugate addition reactions with crowded tri- or
tetrasubstituted electron-deficient alkenes.10 Initially, we
examined the reaction of ethyl glyoxylate oxime 1a, which
is an excellent Michael donor as shown by Jørgensen and
co-workers for the hydroxylation of aliphatic nitroalkenes
by thiourea catalysts,4f with ꢀ-nitroacrylate 2a in the presence
of 20 mol % of organocatalyst 4 (eq 1).
(4) (a) Sekino, E.; Kumamoto, T.; Tanaka, T.; Ikeda, T.; Ishikawa, T.
J. Org. Chem. 2004, 69, 2760. (b) Vanderwal, C. D.; Jacobsen, E. N. J. Am.
Chem. Soc. 2004, 126, 14724. (c) Kano, T.; Tanaka, Y.; Maruoka, K.
Tetrahedron 2007, 63, 8658. (d) Sunde´n, H.; Ibrahem, I.; Zhao, G.-L.;
Eriksson, L.; Co´rdova, A. Chem.sEur. J. 2007, 13, 574. (e) Bertelsen, S.;
Dine´r, P.; Johansen, R. L.; Jørgensen, K. A. J. Am. Chem. Soc. 2007, 129,
1536. (f) Dine´r, P.; Nielsen, M.; Bertelsen, S.; Niess, B.; Jørgensen, K. A.
Chem. Commun. 2007, 3646. (g) Biddle, M. M.; Lin, M.; Scheidt, K. A.
J. Am. Chem. Soc. 2007, 129, 3830. (h) Li, H.; Wang, J.; E-Nunu, T.; Zu,
L.; Jiang, W.; Wei, S.-H.; Wang, W. Chem. Commun. 2007, 507. (i) Wang,
L.-J.; Liu, X.-H.; Dong, Z.-H.; Fu, X.; Feng, X.-M. Angew. Chem., Int. Ed.
2008, 47, 8670. (j) Zu, L.-S.; Zhang, S.-L.; Xie, H.-X.; Wang, W. Org.
Lett. 2009, 11, 1627. (k) Reyes, E.; Talavera, G.; Vicario, J. L.; Badia, D.;
Carrillo, L. Angew. Chem., Int. Ed. 2009, 48, 5701. (l) Wang, H.-F.; Cui,
H.-F.; Chai, Z.; Li, P.; Zheng, C.-W.; Yang, Y.-Q.; Zhao, G. Chem.sEur.
J. 2009, 15, 13299. (m) Gu, Q.; Rong, Z.-Q.; Zheng, C.; You, S.-L. J. Am.
Chem. Soc. 2010, 132, 4056. (n) Matoba, K.; Kawai, Hiroyuki; Furukawa,
T.; Kusuda, A.; Tokunaga, E.; Nakamura, S.; Shiro, M.; Shibata, N. Angew.
Chem., Int. Ed. 2010, 49, 5762.
Although disappointed by the poor reaction outcome
with only a trace amount of the desired product, this
encouraged us to believe that this protocol should be
achieved if the nucleophilicity of the oxime could be
enhanced. Gratifyingly, by simply changing the oxime
from 1a to the relatively more nucleophilic p-methoxy-
benzaldehyde oxime 1b, we obtained the desired product
in 81% yield with 17% ee (Table 1, entry 1).11 Interest-
ingly, decreasing the catalyst loading greatly improved
the stereoselectivity of the reaction (entries 2 vs 1).
We then embarked on optimizing the reaction conditions.
For example, a solvent investigation revealed that nonploar
solvents were superior to polar solvents in terms of yields
and enantioselectivities (entries 1-10). Toluene was found
to be the best solvent (entry 2, 75% yield and 50% ee). After
screening a number of organocatalysts, cinchona alkaloids
5 and 6 bearing a C6′-hydroxy group developed by the Deng
group,12 were identified to be the best organocatalysts for
this conjugate addition.13 With 5 mol % 5 or 6, the reaction
(5) For selected reviews and examples on sulfa-Michael reactions, see:
(a) Wang, X.-F.; Hua, Q.-L.; Cheng, Y.; An, X.-L.; Yang, Q.-Q.; Chen,
J.-R.; Xiao, W.-J. Angew. Chem., Int. Ed. 2010, 49, 8379. (b) Hui, Y.-H.;
Jiang, J.; Wang, W.-T.; Chen, W.-L.; Cai, Y.-F.; Lin, L.-L.; Liu, X.-H.;
Feng, X.-M. Angew. Chem., Int. Ed. 2010, 49, 4290. (c) Liu, Y.; Sun, B.;
Wang, B.; Wakem, M.; Deng, L. J. Am. Chem. Soc. 2009, 131, 418. (d)
Kimmel, K. L.; Robak, M. T.; Ellman, J. A. J. Am. Chem. Soc. 2009, 131,
8754. (e) Wang, J.; Xie, H.-X.; Li, H.; Zu, L.-S.; Wang, W. Angew. Chem.,
Int. Ed. 2008, 47, 4177. (f) Enders, D.; Luttgen, K.; Narine, A. Synthesis
2007, 959. RAJIV(5) For recent phosphite addition reactions and reviews,
see: (g) Zhu, Y.; Malerich, J. P.; Rawal, V. H. Angew, Chem., Int. Ed.
2010, 49, 153. (h) Wang, J.; Heikkinen, L. D.; Li, H.; Zu, L.; Jiang, W.;
Xie, H.; Wang, W. AdV. Synth. Catal. 2007, 349, 1052. (i) Terada, M. T.;
Ube, I. H. J. Am. Chem. Soc. 2007, 129, 14112. (j) Almasi, D.; Alonso,
D. A.; Najera, C. Tetrahedron: Asymmetry 2007, 18, 299. (k) Tsogoeva,
S. B. Eur. J. Org. Chem. 2007, 1701. (l) Vicario, J. L.; Badia, D.; Carrillo,
L. Synthesis 2007, 2065. For recent aza-Michael reactions and review, see:
(m) Roy, S. R.; Chakraborti, A. K. Org. Lett. 2010, 12, 3866. (n) Gogoi,
S.; Zhao, C.-G.; Ding, D.-R. Org. Lett. 2009, 11, 2249. (o) Lin, Q.-Y.;
Meloni, D.; Pan, Y.-C.; Xia, M.; Rodgers, J.; Shepard, S.; Li, M.; Galya,
L.; Metcalf, B.; Yue, T.-Y.; Liu, P.-L.; Zhou, J.-C. Org. Lett. 2009, 11,
1999. (p) Enders, D.; Wang, C.; Liebich, J. X. Chem.sEur. J. 2009, 15,
11058.
(9) (a) Liu, T.-Y.; Li, R.; Chai, Q.; Long, J.; Li, B.-J.; Wu, Y.; Ding,
L.-S.; Chen, Y.-C. Chem.sEur. J. 2006, 13, 319 For reviews, see. (b)
Juaristi, E.; Soloshonok, V. EnantioselectiVe Synthesis of ꢀ-Amino Acids,
2nd ed.; Wiley-VCH: New York, 2005. (c) Abele, S.; Seebach, D. Eur. J.
Org. Chem. 2000, 1.
(6) For intermolecular conjugate addition of heteroatom-based nucleo-
philes with ꢀ,ꢀ-disubstituted R,ꢀ-unsaturated systems see: (a) Emori, E.;
Arai, T.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1998, 120, 4043. (b)
Lu, H.-H.; Zhang, F.-G.; Meng, X.-G.; Duan, S.-W.; Xiao, W.-J. Org. Lett.
2009, 11, 3946. Other oxygen-nucleopiles take part in intermolecular
conjugate addition, for examples, see: (c) Seagers, W. J.; Elving, P. J. J. Am.
Chem. Soc. 1949, 71, 2947. (d) Fuer, H.; Markofsky, S. J. Org. Chem.
1964, 29, 929. (e) Duffy, J. L.; Kurth, J. A.; Kurth, M. J. Tetrahedron Lett.
1993, 34, 1259. (f) Dulcere, J. P.; Dumez, E. Chem. Commun. 1997, 971.
(g) Adderley, N. J.; Buchanan, D. J.; Dixon, D. J.; Laine, D. I. Angew.
Chem., Int. Ed. 2003, 42, 4241. (h) Yi, C.-S.; Yun, S.-S.; He, Z.; Guzei,
I. A. Organometallics 2003, 22, 3031. (i) Buchanan, D. J.; Dixon, D. J.
Org. Lett. 2004, 6, 1357. (j) Xiong, X.; Ovens, C.; Pilling, A. W.; Ward,
J. W.; Dixon, D. J. Org. Lett. 2008, 10, 565.
(10) Quite recently, Scheidt and coworkers developed an elegant
N-heterocyclic carbene-catalyzed conjugate additions of alcohols to enones,
see: Phillips, E. M.; Riedrich, M.; Scheidt, K. A. J. Am. Chem. Soc. 2010,
132, 13179.
(11) In our hands, the conjugate addition adducts are stable and could
be directly subjected to silical gel chromatography. We believe that the
electron-withdrawing ester group has a stabilizing effect as reversible
conjugate addition was observed in the case of simple nitroalkenes by
Jørgensen and coworkers, see ref 4f.
(12) (a) Li, H.-M.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem. Soc.
2004, 126, 9906. (b) Li, H.-M.; Wang, Y.; Tang, L.; Wu, F.-H.; Liu, X.-F.;
Guo, C.-Y.; Foxman, B.-M.; Deng, L. Angew. Chem., Int. Ed. 2005, 44,
105. (c) Liu, X.-F.; Li, H.-M.; Deng, L. Org. Lett. 2005, 7, 167. (d) Li,
H.-M.; Wang, B.-M.; Deng, L. J. Am. Chem. Soc. 2006, 128, 732. See
also: (e) Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am.
Chem. Soc. 1999, 121, 10219. For reviews on cinchona alkaloid catalysis,
see: (f) Chen, Y.-G.; McDaid, P.; Deng, L. Chem. ReV. 2003, 103, 2965.
(g) Tian, S.-K.; Chen, Y.-G.; Chen, J.-F.; Tang, L.; Mcdaid, P.; Deng, L.
Acc, Chem, Res. 2004, 37, 621. (h) Chen, Y.-C. Synlett 2008, 1919.
(13) Please view the Supporting Information for details.
(7) For recent reviews on asymmetric synthesis of tertiary alcohols, see:
(a) Hatano, M.; Ishihara, K. Synthesis 2008, 1647. (b) Riant, O.; Hannedouche,
J. Org. Biomol. Chem. 2007, 5, 873. (c) Cozzi, P. G.; Hilgraf, R.;
Zimmermann, N. Eur. J. Org. Chem. 2007, 5969.
(8) Reviews of asymmetric organocatalytic 1,4-conjugate additions: (a)
Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701. (b) Almasi, D.; Alonso,
D. A.; Na´jera, C. Tetrahedron: Asymmetry 2007, 18, 299.
Org. Lett., Vol. 12, No. 24, 2010
5637

Table 1. Asymmetric Conjugate Addition of Oxime 1b with
ꢀ-Nitroacrylate 2a under Various Conditionsa
Table 2. Asymmetric Conjugate Addition of Oxime 1b to
Various ꢀ-Nitroacrylates 2 in the Presence of 5 mol % of
Organocatalyst 5a
entry
solvent
catalyst
h
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
toluene
toluene
xylenes
benzene
DCM
DCE
CHCl3
Et2O
CH3CN
EtOH
toluene
toluene
toluene
4
4
4
4
4
4
4
4
4
4
5
5
6
26
30
36
36
24
24
24
48
48
72
12
20
24
81
75
91
71
82
86
77
59
47
45
75
77
75
17d
50e
35
50
40
33
45
38
15
9
10
11
12
13
9
-95
-96e
94e
a Unless noted, reactions were carried out with 1b (0.75 mmol), 2 (0.25
mmol) and 5 (5 mol %) in 1.0 mL of toluene at 5 °C. b Isolated yield.
c Determined by chiral HPLC. d Absolute configuration of 3j was determined
by X-ray analysis. e Conducted at 0 °C. f Conducted at -25 °C.
a Unless noted, reactions were carried out with 1b (0.75 mmol), 2a
(0.25 mmol) and 4-6 (10 mol %) in 1.0 mL of solvent at 5 °C. b Isolated
yield. c Determined by chiral HPLC. d Twenty mol % of catalyst was used.
e Five mol % of catalyst was used.
between oxime 1b and ꢀ-nitroacrylate 2a proceeded smoothly
to produce the corresponding products in high yield and
excellent enantioselectivities but with opposite stereochem-
istry (entries 12 and 13).
Scheme 1. Effect of the Olefin Geometry of ꢀ-Nitroacrylate
Under these optimized conditions, the synthetic scope of
the conjugate addition was evaluated, and the results are
presented in Table 2. Changing the ester group of the
ꢀ-nitroacrylate component 2, from ethyl to gradually more
sterically hindered benzyl, i-propyl and t-butyl groups, had
a minor effect on the yields and enantioselectivities (entries
1-4). Most importantly, with 5 mol % of catalyst 5 excellent
enantioselectivities and high yields could be obtained for both
aryl ꢀ-nitroacrylates (entries 1-13) and aliphatic ꢀ-nitroacry-
lates (94-96% ee, entries 14-15).
Furthermore, significant variation in the phenyl ꢀ-ni-
troacrylate 2 architecture can be realized, regardless of steric
or electronic properties, to afford products in 91-98% ee
(entries 4-12). Heteroaryl ꢀ-nitroacrylate could also be
employed in this reaction to yield 96% ee (entry 13). The
configuration of the electron-deficient olefins has significant
influence on the stereoselectivity of the reaction. Control
experiments (Scheme 1) afforded pure (Z)-2o, which reacted
smoothly with 1b and gave the corresponding product 3o in
94% ee, while pure (E)-2o or the (Z)/(E)-mixture of 2o (Z/E
) 2:1) gave poor stereoinductions.
crystallographic analysis, and the newly formed stereogenic
center was assigned to be S accordingly.14 Based on the
experimental results and previous studies,6b we proposed
possible transition state models for this transformation. As
shown in Figure 1, the O-H group of the catalyst may
activate the electrophile through hydrogen bonding interac-
tion, and the oxime attack the Si face of the ꢀ-nitroacrylate
to form the major stereoisomers.
(14) The configuration of 3j was determined by X-ray crystallographic
analysis. CCDC 784524 (3j) 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/daa_
request/cif.
In addition, the absolute configuration of the conjugate
addition product 3j was unambiguously determined by X-ray
5638
Org. Lett., Vol. 12, No. 24, 2010

Scheme 2. Synthetic Applications of the Conjugate Addition
Adducts
In addition, chiral oxazolidin-2-one 10, and ꢀ-lactam 11,12d
could be conveniently accessed from 7 as well.
In conclusion, we have developed a rapid and efficient
method for the catalytic enantioselective construction of
tertiary alcohols through the intermolecular conjugate addi-
tion with synthetically useful enantioselectivities. The adducts
produced by this technique are valuable precursors for
accessing synthetically important chiral building blocks such
as ꢀ2,2-amino acids, oxazolidin-2-ones, ꢀ-lactams, etc.
Figure 1. X-ray crystal structure of compound 3j and proposed
transition states (TS) of the conjugate addition reaction.
Acknowledgment. We are grateful to the National Science
Foundation of China (NO. 21072069 and 21002036) and the
Program for Changjiang Scholars and Innovative Research
Team in University (IRT0953) for support of this research.
The addition adducts 3 from this protocol should be
valuable building blocks for asymmetric synthesis, as they
are highly functionalized with amenable nitro, ester and oxo
groups. For example, cleavage of the weak N-O bond and
simultaneous reduction of the nitro group under mild
condition with 10% Pd/C/H2 cleanly afforded an important
R-hydroxy ꢀ-amino acid ester 7. Subsequent protection with
benzoyl chloride and hydrolysis of the ester group readily
provided the highly desired a ꢀ2,2-amino acid derivative 9.
Supporting Information Available: Experimental pro-
cedures and compound characterization data including X-ray
crystal date (CIF file) for 3j. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL102580N
Org. Lett., Vol. 12, No. 24, 2010
5639