Highly efficient asymmetric Michael addition of aldehydes to nitroalkenes catalyzed by a simple trans-4-hydroxyprolylamide

Article abstract of DOI:10.1002/anie.200602207

Discriminating reactions: While no self-aldol reaction is observed in the reaction shown, catalyst 1 promotes the Michael addition of aldehydes to nitroalkenes with the lowest catalyst loading and lowest stoichiometric ratio of reactant aldehyde that have

Full text of DOI:10.1002/anie.200602207

Communications
Organocatalysis
commercially available. Most importantly, the catalysts are
effective in reactions with nitrostyrenes, but with b-alkyl-
substituted nitroalkenes moderate yields (50%)[8l] or essen-
tially no enantioselectivity (22% ee)[8m] is produced. The need
for high catalyst loading, typically 15–20 mol%, is another
important inconvenience related to most of the above
approaches,[8] specially when the reactions have to be scaled
up. Most recently, an attractive organocatalytic Michael
reaction in brine was disclosed.[8n] Again, low diastereo- and
enantioselectivities (syn/anti 60:40, 38–74% ee) are observed
when aldehydes are employed. Herein we report a new
catalyst design (B, Figure 1) which provides a highly efficient
solution to these problems.
DOI: 10.1002/anie.200602207
Highly Efficient Asymmetric Michael Addition of
Aldehydes to Nitroalkenes Catalyzed by a Simple
trans-4-Hydroxyprolylamide**
Claudio Palomo,* Silvia Vera, Antonia Mielgo, and
Enrique Gómez-Bengoa
Methods based exclusively on organocatalysts have become
of major significance in synthetic chemistry.[1] The Michael
addition of carbonyl compounds to nitroalkenes[2] is a
challenging benchmark for such a development owing to its
À
potential for the construction of a C Cbond with simulta-
neous generation of up to three adjacent stereogenic centers
and because of the pivotal importance of the nitro group as a
precursor to many functionalities.[3] While bifunctional thio-
ureas[4] and chiral Brønsted bases[5] have been developed to
control the stereochemistry of the process with malonate
esters and related methylene-active substrates,[6] stereocon-
trol during the reaction involving aldehydes and ketones is
most often effected from chiral cyclic secondary amines via
enamine formation.[7] However, despite the recent efforts in
the area, unmet challenges remain with regard to substrate
generality and reaction selectivity, including both diastereo-
and enantioselectivity.[8] For example, proline[8a–c] and several
diamine/protonic acid catalysts[8d–h] are capable of promoting
the reactions with ketones, but with aldehydes poor chemical
and stereochemical results are produced (syn/anti 80:20 to
90:10; 70–75% ee). The groups of Kotsuki and Ley have
described a pyrrolidine–pyridine/protonic acid system[8i] and a
homoprolinetetrazole catalyst,[8j,k] which also provide excel-
lent results for ketones. However, very poor enantioselectiv-
ities (22–37% ee) are observed when an aldehyde is used as
the substrate. Highly diastereo- and enantioselective conju-
gate additions involving aldehydes were reported by the
groups of Hayashi and Wang using a diphenylprolinol silyl
ether[8l] and a pyrrolidine–sulfonamide,[8m] respectively. None-
theless, one drawback is the need for a large excess of the
aldehyde substrate, generally 10 equivalents, which becomes
a serious limitation in the case of aldehydes that are not
Figure 1. Features of the catalyst design.
The basis of our proposal stems from the observation that
in the majority of the above catalyst systems a hydrogen-bond
donor at the a-position of the pyrrolidine nitrogen atoms (A,
Figure 1) is introduced to help the catalytic reaction to
proceed.[9] This observation can be correlated to the amine-
catalyzed aldol additions wherein a hydrogen-bond motif
arising from the same position is involved in a half-chair, six-
membered transition state during the catalytic cycle,[10] thus
suggesting that the self-aldol reaction[11] in competition with
the Michael addition could be the reason for most of the
observed problems of the latter. Our hypothesis was that if
the design outlined for B in Figure 1, wherein the a-hydrogen-
bond donor is omitted, could be operative, the aldol reaction
might be kept at a minimum whilst the Michael addition
should proceed with a high degree of diastereo- and
enantiocontrol. To evaluate this hypothesis, trans-4-hydrox-
yprolylamides were selected as potential candidates, as they
meet the proposed structural requirements and, in turn, are
readily available from commercial sources.
To get initial information on the above assumptions,
catalysts 14–20 (Scheme 1) were prepared and screened for
the reaction of trans-nitrostyrene with two representative
aldehydes, butyraldehyde 1a and isovaleraldehyde 1d. With
catalysts 14 and 15, which lack hydrogen-bond donors, the
reaction proceeded to give adducts 8a and 8d with good
diastereoselectivity, albeit with poor enantioselectivity
(Table 1, entries 1 and 2). To our delight, when the same
reactions were carried out in the presence of trans-4-
hydroxyprolylamides 16, 17, and 18, adducts 8a and 8d
were produced with similar diastereoselectivity levels but,
most significantly, with much better enantioselectivities
[*] Prof. Dr. C. Palomo, S. Vera, Dr. A. Mielgo, Dr. E. Gómez-Bengoa
Departamento de Química Orgµnica I
Facultad de Química
Universidad del País Vasco. Apdo. 1072.
20080 San Sebastiµn (Spain)
Fax: (+34)943-015-270
E-mail: claudio.palomo@ehu.es
[**] This work was financially supported by The University of the Basque
Country (UPV/EHU) and the Ministerio de Educación y Ciencia
(MEC, Spain). A predoctoral grant to S.V. from MEC is also
acknowledged. We also thank M. Alcalµ and A. Lizarraga for their
help with some experimental work and the SGI/IZO-SGIker UPV/
EHU for allocation of computational resources.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 2: Michael addition reactions of aldehydes to nitroalkenes cata-
lyzed by 16 and/or 18.[a]
Entry Cat.[b]
Product 8–13
T
t
Yield[c] d.r.[d]
ee
[8C] [h] [%]
(syn/anti) [%]
1
2
18(10)
18(5)
RT
0
2
75
98:2
99:1
94
>99
20 90[e]
3
4
18(10)
18(10)
RT 2.5 67
90:10
95:5
94
96
0
20 72
5
6
18(5)
18(5)
0
0
20 70[e]
20 87[f]
99:1
90:10
96
99
7
8
16(10)
18(10)
RT
RT
20 66[g]
20 75
97:3
95:5
93
91
Scheme 1. Catalytic asymmetric conjugate additions of aldehydes to
nitroalkenes. Bn=benzyl; Cy=cyclohexyl.
9
18(5)
0
20 72[e]
96:4
>99
10
11
16(10)
18(5)
0
0
20 90[g]
20 70
92:8
97:3
76
98
Table 1: Catalyst screening for reaction of 1a and 1d with trans-b-
nitrostyrene (2).[a]
Product 8a (R=Et, R1 =Ph) Product 8d (R=iPr, R1 =Ph)
Entry Cat. Conv.
d.r.[c]
ee
Conv.
d.r.[c]
ee
12
13
18(5)
0
20 70
>99:1
94
92
[%][b]
(syn/anti) [%][c] [%][b]
(syn/anti) [%][c]
1
2
3
4
5
6
7
14 >99
15 >99
16 >99
92:8
92:8
98:2
60
60
86
92
94
–
>99
98:2
40
60
90
90
91
–
99[d] 98:2
50
75
>99
n.r.
96:4
98:2
95:5
–
18(10)
RT
14 76
94:6
17 >99[e] 98:2
18 >99[e] 98:2
19 n.r.[f]
–
14
15
16(10)
18(5)
0
0
20 90[g]
20 72
97:3
>99:1
86
>99
20 >99[e] 96:4
40
>99
90:10
70
[a] Reactions conducted on a 0.25-mmol scale with a tenfold excess of
1
aldehyde and Cl2CH2 as solvent. [b] Determined by H NMR spectros-
copy (500 MHz) after 20–24 h at room temperature. [c] Determined by
HPLC. See the Supporting Information for further details. [d] After 60 h at
room temperature. [e] After 2 h at room temperature. [f] n.r. =no
reaction.
16
18(5)
0
20 75
>99:1
>99
[a] Reactions conducted on a 1-mmol scale in CH2Cl2 (1 mL) when
10 mol% is used and CH2Cl2 (0.5 mL) when 5 mol% of catalyst is used.
[b] Number in parenthesis refers to the catalyst loading in mol%.
[c] Yield of isolated product after column chromatography. [d] Deter-
mined by chiral high-performance liquid chromatography. [e] Reaction
conducted on a 3-mmol scale using 1.2 equivalents of aldehyde.
[f] Reaction conducted on a 20-mmol scale. [g] Conversion determined
by 1H NMR spectroscopy.
(Table 1, entries 3–5). Interestingly, in no case was the
corresponding aldol adduct observed despite the excess of
aldehyde employed.[12] On the other hand, the fact that no
reactions were observed with methyl ether 19 (Table 1,
entry 6) further establishes the importance of the hydroxy
group not only for reaction stereocontrol, but also for catalyst
activity. Furthermore, the position of the hydroxy group in the
catalyst seems also to be important as the 3-hydroxyproyla-
mide derivative 20 led to lower enantio- and diastereoselec-
tivities (Table 1, entry 7).
Results from the reaction of several aldehydes and
nitroalkenes promoted by catalysts 16 and 18 are summarized
in Table 2. While both catalysts provided comparable syn/anti
selectivity ratios, the latter was most effective in terms of
reaction enantioselectivity (Table 2, entries 7/8, 10/11, and 14/
15). The optimum results were achieved when the reactions
were carried out in CH2Cl2 at room temperature in the
presence of 10 mol% of catalyst 18 for b-branched aldehydes
(Table 2, entries 8 and 13) and 5 mol% for linear-chain
aldehydes at 08C. To the best of our knowledge, this finding
represents the lowest catalyst/substrate ratio employed in
enamine-based Michael additions. Under these conditions,
the enantioselectivities obtained were above 90% for essen-
tially all substrates that were explored, including b-alkyl-
substituted nitroalkenes, which gave adducts with diastereo-
meric ratios greater than 99:1 and enantioselectivities of up to
99% (Table 2, entries 15, 16).[13] Furthermore, in these
reactions only a slight excess of the aldehyde substrate (1.5–
2.0 equiv) is employed, but nearly equimolar amounts are also
tolerated with equal efficiency (Table 2, entries 2, 5, and 9).
The utility of this approach is illustrated in the reaction of
heptanal with nitrostyrene performed on a 20-mmol scale
(Table 2, entry 6), which provided 8c with no significant
detrimental effect on yield or stereoselectivity. Moreover, the
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catalyst can be easily recovered in 70–80% yield after the
Keywords: asymmetric synthesis · Michael addition ·
nitro compounds · organocatalysis · synthetic methods
.
reaction by simple aqueous acid/base work up, which is an
additional aspect of the approach that is of practical
importance.
The excellent chemical and stereochemical efficiency
observed in these Michael reactions is also of particular
interest in that it may provide a simple route to 3,4-
disubstituted pyrrolidines[8d] or, as shown in Scheme 2, to g-
butyrolactones, which are common structural units of natural
products.[14]
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Scheme 2. Elaboration of the Michael adducts.
To better understand the efficiency of the present model
the reaction between propionaldehyde and 1-nitropropene
catalyzed by N,N-dimethyl-trans-4-hydroxyprolylamide was
studied by DFT calculations at the B3LYP/6-31G* level.
Concordant with our initial hypothesis, the results show that
the OH group helps to discriminate between the two possible
transition-state (TS) models C and D by 2.1 kcalmolÀ1
(Figure 2) and that in the absence of a hydrogen-bond
donor, the reactions promoted by the naked prolylamide
derivative or the OMe derivative are 103 times slower.[15]
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Figure 2. Models for the TS in the catalytic addition of propionalde-
hyde to 1-nitropropene.
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In conclusion, we have documented a new model for the
catalytic asymmetric Michael addition of aldehydes to nitro-
alkenes which holds several interesting features: a) Michael
adducts with very high diastereo- and enantioselectivity and a
broad range of b-substitution patterns are accessible; b) the
catalyst, which in most cases is used in only 5 mol%, is readily
available and recoverable; and c) almost equimolar amounts
of the aldehyde donor can be employed.
Received: June 2, 2006
Published online: August 4, 2006
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[13] This catalytic system seems to be less effective for ketones; for
instance, using catalyst 18 (10 mol%) and cyclohexanone
(3 equiv) at room temperature gave d.r. 83:17 and 20% ee;
using tetrahydrothiopyran-4-one (10 equiv) at 08Cgave d.r.
> 99:1 and 60% ee. For recent catalysts for ketone additions,
see: homoproline: a) D. Terakado, M. Takano, T. Oriyama,
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amine–thiourea catalysts: c) H. Huang, E. Jacobsen, J. Am.
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Chem. Commun. 2006, 1451 – 1453; primary amines: e) Y. Xei,
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[15] For details, see the Supporting Information.
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