Modularly designed organocatalytic assemblies for direct nitro-Michael addition reactions

Article abstract of DOI:10.1002/anie.200803236

It's so simple! Organocatalysts formed through the self-assembly of simple α-amino acids and alkaloid thiourea derivatives (see scheme) are used as highly efficient catalysts for the direct nitro-Michael addition of ketones and nitroalkenes, affording excellent ee values up to 99%. Enantioselectivity may be tuned by changing components of the self-assembled catalyst.

Full text of DOI:10.1002/anie.200803236

Communications
DOI: 10.1002/anie.200803236
Asymmetric Catalysis
Modularly Designed Organocatalytic Assemblies for Direct Nitro-
Michael Addition Reactions**
Tanmay Mandal and Cong-Gui Zhao*
Organocatalysis has developed rapidly in recent years.[1]
Among the catalysts developed for this purpose, proline
derivatives have risen to prominence, and have been used to
catalyze a wide range of reactions.[2] While covalent bonds are
used to connect the stereocontrolling moiety and the pyrro-
lidine backbone in most of these derivatives, Clarke and
Fuentes recently reported the first example of modularly
designed prolinamide-based catalysts that self-assemble
under the reaction conditions through hydrogen-bonding
interactions.[3] Although the reported method only affords
mediocre enantioselectivities in most cases, the advantage of
this approach is obvious: Modification of the catalyst
structure only needs simple replacement of the modules,
while further chemical synthesis is avoided. Moreover, a
library of diverse organocatalysts may be more efficiently
obtained for catalyst screening and structure modification.[4]
During our recent study of quinine derivative-catalyzed
enantioselective reactions,[5,6] we envisioned that ionic inter-
actions may be utilized for the self-assembly of modularly
designed organocatalysts. Our hypothesis is shown in Equa-
tion (1) with proline as the reaction-center module. When
proline and a tertiary amine carrying a thiourea moiety (the
stereocontrolling module)[7] are mixed, an acid–base reaction
between the carboxylic acid and the tertiary amine groups
should lead to an ammonium salt.[8] Ionic interactions
between the ammonium and the carboxylate should cause
these two modules to self-assemble,[9] forming a potential
organocatalyst incorporating both the proline reaction center
and a stereocontrolling moiety.
À
Michael addition is one of the most important C C bond-
forming reactions in organic synthesis,[10] and many proline
derivatives[11] have been developed as catalysts for the direct
addition of ketones/aldehydes to nitroalkenes since the
proline-catalyzed direct nitro-Michael addition was discov-
ered.[12] To test our hypothesis, the nitro-Michael addition
reaction was adopted as a model. Herein we wish to report
our preliminary results of using these self-assembled organo-
catalysts in the direct Michael addition of ketones and
aldehydes to nitroalkenes.
Acetone and trans-b-nitrostyrene were selected as the
model substrates in the preliminary screening. Acetone is one
of the most problematic substrates for the nitro-Michael
addition. To our knowledge, enantiomeric excesses of over
90% have been obtained for the Michael product with an
acetone substrate in only two cases[11i–j], despite the fact that
numerous sophisticated proline derivatives have been
reported as the organocatalysts for this reaction.[11p–q] Readily
available a-amino acids, such as proline, glycine, alanine, l-
tert-leucine, and phenylglycine,[13] were selected as the
reaction-center modules, whereas some readily accessible
cinchona alkaloid derivatives were chosen as the stereocon-
trolling modules (Scheme 1). Some typical results[13] are
summarized in Table 1.
The enantiomers of proline show strong matching and
mismatching effects with the thiourea derivative Q-1
(Scheme 1): No conversion of trans-b-nitrostyrene was
detected after 72 h when l-proline was used (Table 1,
entry 1). In contrast, after only 20 h, the desired product
was obtained in 88% yield and 66% ee for the r enantiomer
when d-proline (Table 1, entry 2) was used under the same
conditions. Nonetheless, poor conversions were achieved
when either Q-1 (0%) or d-proline (< 5%) were used
alone.[13] Thiourea derivatives Q-2 and Q-3 (see Scheme 1)
generate similar results to Q-1 with d-proline (Table 1,
entries 3 and 4). In contrast, similar precatalyst modules
without the thiourea moiety were not effective in promoting
enantioselectivity. For examples, Q-4, Q-5, and Q-6 (see
Scheme 1) and d-proline all lead to much inferior ee values
(Table 1, entries 5–7). These results indicate that this catalytic
system is different from the reported asymmetric counterion-
directed catalysis (ACDC),[8] as, in the case of ACDC, the
stereocontrol is achieved mainly through steric effects instead
of hydrogen-bonding.
[*] Dr. T. Mandal, Prof. Dr. C.-G. Zhao
Department of Chemistry
University of Texas at San Antonio
One UTSA Circle, San Antonio, TX 78249 (USA)
Fax: (+1)210-458-7428
E-mail: cong.zhao@utsa.edu
Homepage: http://www.utsa.edu/chem/faculty/zhao.cfm
The reaction conditions were then optimized for the self-
assembly of Q-1 and d-proline and we were surprised to find
that improved enantioselectivity (78% ee) of the product may
be obtained by reducing the catalyst loading to 5 mol%.[13]
[**] We thank the Welch Foundation (Grant No. AX-1953) for the
financial support of this project.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200803236.
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Chemie
results.[15] For example, the achiral a-amino acid
glycine was found to self-assemble with Q-1, too.
Although this assembly is not very reactive, the
enantioselectivity obtained is a very promising
51% ee for the S-configured product (Table 1,
entry 12). The self-assembly of l-alanine and Q-1
also reacts, albeit in very low efficiency (Table 1,
entry 13). Further such screenings[13] identified
the assembly of l-phenylglycine and QD-1 as a
highly enantioselective catalyst, affording the R-
configured Michael adduct in 95% ee (Table 1,
entry 14).
In contrast, proline derivatives that do not
self-assemble with QD-1, such as methyl l-
Scheme 1. Structure of representative precatalyst modules.
prolinate and l-prolinamide, fail to generate the
desired product in good yields and ee values
under similar conditions.[13] These results clearly
Table 1: Michael addition of acetone to trans-b-nitrostyrene catalyzed by
evince that catalytic activity and directing effects are, in this
case, the result of the self-assembled catalysts instead of
synergistic effects.[14] Moreover, this conclusion is also sup-
ported by NMR spectroscopy[13] of the l-proline and QD-1
mixture. The scope of this approach was then evaluated,
under the optimized conditions, with various ketone, alde-
hyde, and nitroalkene substrates. Some typical results with
ketones and nitrostyrenes are compiled in Table 2.[15] The
reaction of acetone with b-nitrostyrene derivatives, under the
catalysis of the assembly of l-phenylglycine and QD-1,
affords excellent enantioselectivities (ꢀ 94% ee, Table 2,
entries 1–8). However, this assembly is not very reactive for
most other ketone substrates, although when reaction does
occur, it is with very high enantioselectivity in the product
(Table 2, entry 9). While the assembly of l-proline and QD-1
leads to slightly inferior ee values for an acetone substrate,[15]
it is much more reactive under similar conditions. This
assembly is a good catalyst for longer-chain ketone substrates,
such as methyl ketones (Table 2, entries 10–13)and 3-penta-
none (Table 2, entry 14), and cyclic ketones, such as cyclo-
pentanone (Table 2, entry 15) and cyclohexanone derivatives
(Table 2, entries 16–18). The syn diastereomers were obtained
in good diastereoselectivity in all cases, except for 4-methyl-2-
pentanone, which produces the kinetic (anti) product
(Table 2, entry 13). Excellent ee values and good diastereo-
selectivities may also be achieved with aldehyde and aliphatic
nitroalkene substrates by using this catalytic system.[15]
The opposite senses of enantioselectivity and diastereo-
selectivity for the assemblies of l-proline and l-phenyglycine
with QD-1 may be rationalized by the proposed transition
states, as shown in Scheme 2. In the case of l-proline, the
Si,Si-attack of the hydrogen-bonded nitrostyrene on the anti
rotamer of the E-enamine intermediate leads to the (3R,4S)-
configured major syn diastereomer (Scheme 2, upper struc-
ture). In contrast, in the case of l-phenyglycine, formation of
a Z-enamine is favored,[11j] and the Re,Si-attack of the
hydrogen-bonded nitrostyrene on this enamine leads to the
major (3R,4R)-configured anti product (Scheme 2, lower
structure).
self-assembled catalysts.[a]
Entry
Module/Loading
(mol%)
t [h]
Yield [%][b]
ee [%][c]
(configuration)
1
2
3
4
5
l-Pro/20
d-Pro/20
d-Pro/20
d-Pro/20
d-Pro/20
d-Pro/20
d-Pro/20
d-Pro/5
l-Pro/5
l-Pro/5
d-Pro/5
Gly/20
Q-1/20
72
20
22
24
30
40
32
120
72
72
0
88
83
83
78
87
79
67
81
75
13[f]
13[f]
5[f]
63
–
Q-1/20
Q-2/20
Q-3/20
Q-4/20
Q-5/20
Q-6/20
Q-1/5
QD-1/5
QD-2/5
QD-1/5
Q-1/20
Q-1/20
QD-1/5
66 (R)
66 (R)
67 (R)
11 (S)
11 (R)
5 (R)
86 (R)
86 (S)
86 (S)
40 (R)
51 (S)
6 (S)
6
7
8[d]
9[e]
10[d]
11[e]
12
13
14[e]
120
120
120
192
l-Ala/20
l-PhGly/5
95 (R)
[a] Unless otherwise indicated, all reactions were conducted with trans-b-
nitrostyrene (0.1 mmol), acetone (0.7 mmol, 50 mL), and the precatalyst
combinations in CH2Cl2 (1.0 mL) at room temperature. [b] Yield of
isolated product after column chromatography. [c] Determined by HPLC
analysis on a ChiralPak AD-H column. Absolute configuration was
determined by comparison with the reported optical rotation data.
[d] Conducted in benzene (1.0 mL) at 28C. [e] Conducted in benzene
(1.0 mL) at room temperature. [f] Conversion as determined by 1H NMR
analysis.
Through further optimization of the reaction conditions,[13]
a
highest ee value of 86% of the product may be obtained in
benzene at approximately 28C (Table 1, entry 8).
As expected, quinidine thioureas, such as QD-1 and QD-
2, match with l-proline for this reaction. The reaction
catalyzed by the organocatalyst assembly of QD-1 and l-
proline yields the anticipated S enantiomer in 86% ee at room
temperature in benzene (Table 1, entry 9). Similar results
were obtained for the assembly of QD-2 and l-proline
(Table 1, entry 10). The mismatched assembly of d-proline
and QD-1 again delivered poor results (Table 1, entry 11).
Besides proline, some a-amino acids with a primary amine
group were also screened, delivering some very interesting
In summary, we have demonstrated that ionic interactions
between ammonium and carboxylate ions may be utilized for
the formation of organocatalytic self-assemblies from readily
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Table 2: Direct nitro-Michael addition of ketones to nitrostyrenes catalyzed by the self-assemblies.[a]
enantioselective
direct
nitro-
Michael addition of ketones and
aldehydes to nitroalkenes.
Experimental Section
Entry
R1
R2
X
t [d]
Yield [%][b]
d.r.[c]
ee [%][d]
(configuration)
General Procedure: The precatalysts l-
proline (or d-proline, 0.005 mmol,
0.6 mg, or l-phenylglycine, 0.005 mmol,
0.8 mg) and Q-1 (or QD-1, 3.0 mg,
1
2
3
4
5
6
7
H
H
H
H
H
H
H
H
H
H
H
H
iPr
Me
H
H
H
H
H
H
H
H
Me
Me
Et
OMe
H
H
4-Cl
4-Br
4-Me
4-MeO
3-Cl
2-Br
2-NO2
H
H
H
H
H
8
8
8
8
8
8
8
8
63
57
59
61
55
55
63
69
40
78
72
51
53
47
63
92
75
76
–
–
–
–
–
–
–
–
95 (R)
95 (R)
94 (R)
94 (R)
0.005 mmol),
trans-b-nitrostyrene
(0.1 mmol, 14.9 mg) and benzene
(1 mL) were added to a capped 8 mL
sample vial. The resulting mixture was
stirred for 1 min at room temperature
before acetone (0.7 mmol, 50 mL) was
added with a Hamilton syringe. The
reaction mixture was further stirred at
room temperature for the time as speci-
fied in Table 1 (monitored by TLC), and
96 (R)
95 (R)
98 (R)[e]
97 (R)
8
9[f]
8
25:75
96:4
90:10
82:18
–
88:12
77:23
93:7
90:10
96:4
99 (R,R)[g]
90 (R,S)[g]
94 (R,S)[g]
90 (R,S)[g]
86 (S)
10[f,h]
11[f,h]
12[f,h]
13[f,h]
14[h]
15[h,i]
16[h,i]
17[h,i]
18[h,i]
3.5
3.5
4
5
7
5
3
4
3.5
then directly transferred to
a short
column packed with silica gel. The
column was eluted with 9:1 hexane/
ethyl acetate mixture and the solvent
was removed under reduced pressure,
affording the direct nitro-Michael addi-
tion product as a pure compound.
Me
H
H
H
H
90 (R,S)
92 (R,S)
84 (R,S)
94 (S,S)
99 (R,S)
-(CH2)2-
-(CH2)3-
-CH2OCH2-
-CH2SCH2-
H
[a] Unless otherwise indicated, all reactions were conducted with trans-b-nitrostyrene (0.1 mmol),
ketone (0.7 mmol), and the catalyst assembly of QD-1 and l-phenylglycine (5 mol% loading each) in
benzene (1.0 mL) at room temperature. [b] Yield of the isolated product after column chromatography.
Received: July 3, 2008
Published online: September 2, 2008
1
[c] Ratio of syn/anti as determined by H NMR analyses of the crude products. [d] Unless otherwise
indicated, ee values were determined by HPLC analysis on a ChiralPak AD-H column; absolute
configurations were determined by comparison with the reported optical rotation data or tentatively
assigned on the basis of the reaction mechanism. [e] Separated on a ChiralPak AS column. [f] Only the
given regioisomer was obtained in the crude product. [g] Separated on a Chiralcel OD-H column. [h] The
catalyst assembly used was l-proline and QD-1 (5 mol% loading each). [i] 0.15 mmol of ketone was
used.
Keywords: alkaloids · amino acids ·
.
asymmetric synthesis ·
Michael addition · organocatalysis ·
self-assembly
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