Highly enantioselective organocatalytic Michael addition of nitroalkanes to 4-oxo-enoates

Article abstract of DOI:10.1039/b905033g

A useful Michael addition reaction using nitroalkanes as the nucleophile and 4-oxo-enoates as the Michael acceptor has been disclosed, and the reaction allows expedient access to functionalized chiral γ-keto esters in high yields and excellent enantioselectivities (up to 98% ee), with a low catalyst loading.

Full text of DOI:10.1039/b905033g

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Highly enantioselective organocatalytic Michael addition of nitroalkanes
to 4-oxo-enoatesw
Hai-Hua Lu, Xu-Fan Wang, Chang-Jiang Yao, Jian-Ming Zhang, Hong Wu
and Wen-Jing Xiao*
Received (in Cambridge, UK) 11th March 2009, Accepted 19th May 2009
First published as an Advance Article on the web 10th June 2009
DOI: 10.1039/b905033g
A useful Michael addition reaction using nitroalkanes as the
nucleophile and 4-oxo-enoates as the Michael acceptor has
been disclosed, and the reaction allows expedient access to
functionalized chiral c-keto esters in high yields and excellent
enantioselectivities (up to 98% ee), with a low catalyst loading.
The conjugate addition of carbon nucleophiles to activated
unsaturated systems has become a classic and fundamental
bond-forming reaction in organic synthesis since its discovery
in 1887.1 The broad spectrum of potential donors and
Scheme 1 Asymmetric nitro-Michael additions with 4-oxo-enoates.
acceptors makes this reaction exceptionally versatile and a
wide range of synthetically useful adducts bearing various
functional groups can be generated. In this context, the
employment of nitroalkanes as a nucleophilic donor has
drawn enormous attention from the chemical community2
because of the easy manipulation of the nitro functionality
into amines (reduction), hydrides (radical denitration),
aldehydes, ketones (Nef reaction), and other valuable building
blocks.3 While numerous efficient nitro-Michael reactions
have been developed and widely applied in the synthesis of
complex targets, developing catalytic asymmetric variants
continues to be an important challenge.
Recently, highly enantioselective nitro-Michael additions
Fig. 1 The bifunctional organocatalysts examined in this study.
with enones,4 enals,5 nitroalkenes,6 and a,b-unsaturated
(up to 98% ee),12 further manipulations of which would lead
to optically active b2-amino acids (Scheme 1).13,14
amides7 and esters,8 were accomplished by either metallic
catalysis or organocatalysis.9 Despite advances being made,
issues concerning substrate dependence, reaction efficiency
and selectivity remain elusive; the intrinsic potential of the
nitro-Michael reaction has not been fully achieved compared
with its parallel nitro-aldol10 or nitro-Mannich reactions.11
The development of highly enantioselective nitro-Michael
additions of novel unsaturated systems with multifunctional
groups and their transformations to synthetically valuable
compounds is highly desirable. In this communication, we
present an organocatalytic nitro-Michael addition of nitro-
alkanes to 4-oxo-enoates by means of acid–base catalysis,
Our investigations started with the reaction between
(E)-ethyl-4-phenyl-4-oxo-but-2-enoate (1a) and nitromethane
(2a), and the best result (12 h, 95% yield and 96% ee) was
obtained with 5 mol% of bifunctional Cinchona alkaloid-
based thiourea catalyst VII (see Fig. 1) in xylenes at ambient
temperature (Table 1, entry 15).15
With optimal conditions in hand, we then evaluated the
generality of this protocol and the results are summarized in
Table 2. As shown in entries 1–4, the reaction appears quite
general with respect to the ester group of 4-oxo-enoates. This
reaction is general with respect to the benzene architecture of
4-oxo-enoates as well. The steric properties of the aryl 4-oxo-
enoates have a minimal impact on the stereoselectivity
(entries 5–8). Moreover, further decreasing the catalyst
loading, from 5 mol% to 2 mol% of VII, is feasible with no
influence on the enantio-outcome (entry 5 vs. 6). Variation in
the electronic nature of the aromatic ring systems is possible.
Relatively electron-neutral (entries 1–4), electron-withdrawing
(entries 5–8 and 12–16) or electron-donating groups
(entries 9–11) on the benzene ring can be tolerated. Other
4-heteroaryl-4-oxo-but-2-enoates can be also employed in this
a nice combination to generate chiral g-keto esters
with complete regioselectivity and high enantioselectivity
Key Laboratory of Pesticide & Chemical Biology, Ministry of
Education, College of Chemistry, Central China Normal University,
152 Luoyu Road, Wuhan, Hubei 430079, China.
E-mail: wxiao@mail.ccnu.edu.cn; Fax: (+86) 27-67862041;
Tel: (+86) 27-67862041
w Electronic supplementary information (ESI) available: Experimental
procedures and compound characterization data, including X-ray
crystal data for 3n. CCDC 712054. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/b905033g
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Table 1 Asymmetric Michael additions of nitromethane (2a) to
(E)-ethyl-4-phenyl-4-oxo-but-2-enoate (1a) under various conditionsa
Table 2 Organocatalytic asymmetric Michael addition reactions of
nitroalkanes 2 with 4-oxo-enoates 1 by catalyst VIIa
Entry
Catalyst
Solvent
Toluene
t/h
Yield (%)b
Ee (%)c
Yield
(%)b
Entry
R1
R2
R3
R4
Ee (%)c
1
2
3
4
5
6
7
I
II
6
86
38
23
90
91
88
87
ꢂ53
ꢂ52
ꢂ70
ꢂ80
ꢂ80
91
90
90
6
5
5
1
2
3
4
Ph
Ph
Ph
Ph
Et
Me
i-Pr
Bn
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Bn
Et
Et
Et
Et
Et
Et
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
3a
3b
3c
3d
3e
3e
3f
3g
3h
3i
95
89
97
98
94
78
95
65
84
91
93
93
96
91
85
90
92
86
47
89
99
96
96
96
96
97
97
98
91
98
94
96
96
97
97
97
97
III
IV
V
VI
VII
5
p-NO2Ph
p-NO2Ph
m-NO2Ph
o-NO2Ph
p-MeOPh
m-MeOPh
p-MePh
p-FPh
p-ClPh
p-BrPh
p-BrPh
m-BrPh
2-Furanyl
2-Thienyl
t-Bu
5
96
6d
7
8
9
VII
Xylenes
Mesitylene
Hexane
Et2O
i-PrOH
Neat
H2O
6
24
5
24
24
3
4
12
90
91
84
83
78
86
85
95
96
96
93
95
84
93
88
96
8
9
10
11
12
13
14
15d
10
11
12
13
14
15
16
17
18
19e
20f
21g
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
Xylenes
a
Reactions were carried out with 1a (0.25 mmol), nitromethane 2a
(1.25 mmol) and catalyst I–VII (10 mol%) in solvent (0.5 mL) at
H
H
H
Me
CO2Et
97
98
80
97, 96
68, 92
b
RT. Isolated yield. Determined by chiral HPLC. 5 mol% of VII
c
d
was used. RT = room temperature.
Ph
Ph
a
reaction with excellent results being obtained (entries 17
and 18). Notably, less active 4-alkyl substituted 4-oxo-enoate
1r can be used as a Michael acceptor for this transformation,
and the corresponding adduct, 3r, was obtained in 80% ee
(entry 19). Perhaps more importantly, nitroalkanes other than
nitromethane, can be used as Michael donors in this addition.
Preliminary experiments with nitroethane (2b) and ethyl
2-nitropropionate (2c) revealed that the corresponding
products were effectively obtained in high yields and great
enantioselectivities, with moderate diastereoselectivities
(entries 20 and 21). It is worth noting that adjacent quaternary
and tertiary stereocentres were constructed in the latter case.
To determine the absolute configuration of the product, 3n
was obtained as a white crystal from a mixture of hexane and
ethyl acetate. The absolute configuration of the newly formed
stereocentre in compound 3n was then unambiguously deter-
mined to be R by X-ray crystallographic analysis (Fig. 2).16
b-Amino acids are common units found in natural products
and pharmaceuticals.13 Recent studies have revealed that
many peptides containing b-amino acid residues show well-
defined secondary structures and display useful biological
activities. However, to date, only b3-amino acids are commer-
cially available with a broad spectrum of substituents. In
contrast, b2-amino acids seem harder to prepare and their
synthesis remains a challenge.14 In principle, the current
protocol could be used as the key step for the synthesis of
b2-amino acids. Accordingly, 3a, 3d and 3h were, respectively,
prepared in the presence of 3 mol% of VII on gram scales
(Scheme 2 and eqn 1). Keto protection of 3a and 3d were
accomplished either with glycol or 1,2-ethanedithiol.
Following known procedures, one-pot desulfurization and
hydrogenation of 5 by the classical RANEYs nickel method
would afford (S)-2-(aminomethyl)-4-phenyl-butanoic acid
(6).17 Meanwhile, a two-step sequence, NiCl2ꢁ6H2O–NaBH4
Reactions were carried out with 4-oxo-enoates 1 (0.25 mmol),
nitroalkanes 2 (1.25 mmol, 2a: R3 = R4 = H; 2b: R3 = CH3,
R4 = H; 2c: R3 = CH3, R4 = CO2Et) and catalyst VII (5 mol%)
b
c
in xylenes (0.5 mL) at RT. Isolated yield. Determined by chiral
d
HPLC. 2 mol% of VII was used. 10 mol% of VII was used.
g
d.r. = 65 : 35. d.r. = 81 : 19. d.r. = diastereomeric ratio.
e
f
Fig. 2 X-Ray crystal structure of nitro-Michael adduct 3n.
Scheme 2 Synthesis of b2-amino acid derivatives.
reduction and subsequent amine protection, provided the
desired product 7 in 80% yield. In addition, by subjecting 3h
to Baeyer–Villiger conditions, we successfully obtained
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succinate 8,
a
valuable precursor for the synthesis of
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(R)-2-(aminomethyl)butanedioic acid (9)18a and b-proline
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ð1Þ
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In summary, we have developed a nitro-Michael reaction
with 4-oxo-enoates in excellent enantioselectivities and
demonstrated its value in the expedient synthesis of b2-amino
acid derivatives. The reaction itself is completely atom-
economic and involves simple experimental procedures under
benign conditions with low loadings of a bench-stable catalyst.
We are grateful to the National Science Foundation of
China (20672040 and 20872043), the Program for Academic
Leader in Wuhan Municipality (200851430486), and the
Program for New Century Excellent Talents in University
(NCET-05-0672) for support of this research. We thank
Dr Xiang-Gao Meng for X-ray analysis.
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A, a = 90, b = 90.031(1), g = 901, V = 1776.6(5) A3, Dcalc
=
1.519 Mg/m3, T = 292(2) K, Z = 4, 8715 reflections collected,
5418 independent (Rint = 0.0852), final R indices [I 4 2s(I)]: R1 =
0.0514, wR2 = 0.1200, R indices (all data): R1 = 0.0835, wR2
=
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Chem. Commun., 2009, 4251–4253 | 4253