Simple highly modular acyclic amine-catalyzed direct enantioselective addition of ketones to nitro-olefins

Article abstract of DOI:10.1039/b514783m

Simple, highly modular primary amino acid derivatives catalyze the direct enantioselective addition of ketones to nitro-olefins with high stereocontrol and furnish the corresponding aldol products in high yield with up to >38 : 1 dr and up to 99% ee. The

Full text of DOI:10.1039/b514783m

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Simple highly modular acyclic amine-catalyzed direct enantioselective
addition of ketones to nitro-olefins{
Yongmei Xu and Armando Co´rdova*
Received (in Cambridge, UK) 18th October 2005, Accepted 17th November 2005
First published as an Advance Article on the web 13th December 2005
DOI: 10.1039/b514783m
2a (0.25 mmol) in wet DMSO (1 mL + 45 mL H2O) (Table 1). A
small amount of water (0.025 mmol) was added since we have
found that it significantly accelerates as well as improves the
stereoselectivity of primary amine-catalyzed asymmetric C–C
bond-forming reactions.11
Simple, highly modular primary amino acid derivatives catalyze
the direct enantioselective addition of ketones to nitro-olefins
with high stereocontrol and furnish the corresponding aldol
products in high yield with up to >38 : 1 dr and up to 99% ee.
The Michael reaction is an important carbon–carbon bond-
forming reaction in organic synthesis.1 As a consequence several
catalytic asymmetric protocols have been developed for this
fundamental reaction.2 In recent years, an intense research effort
has been made to find non-toxic chiral organic molecules as
catalysts for enantioselective reactions.3 In this context, proline4
and N-terminal prolyl peptides5 have been described as catalyst for
the asymmetric Michael reaction. However, only moderate
enantioselectivity is typically obtained with these natural catalysts.
Proline derivatives on the other hand have been proven to be
highly successful for the asymmetric nitro-Michael reaction.6–9
However, they are generally more complex and prepared in more
steps than simple amino acid or peptide catalysts. Herein, we
present that simple and highly modular amino acid derivatives
with a catalytic primary amine residue catalyze the direct
asymmetric Michael addition of ketones to nitro-olefins with high
stereoselectivity and furnish the corresponding c-nitroketones with
up to >38 : 1 dr and 99% ee.
Notably, almost all the simple chiral amines 4–15 mediated the
formation of the Michael product 3a under the set reaction
conditions and several of the amino acids exhibited high
stereoselectivity for the transformation. For example, alanine
derived catalysts 11 and 14 catalyzed the asymmetric formation of
3a with 14 : 1 dr and 35: 1 dr, respectively, and 91% ee. In
comparison, (S)-alanine furnished Michael product 3a in trace
amounts after 24 h with 6 : 1 dr and 81% ee. Furthermore, we
Table 1 Examples of screened catalysts for the direct asymmetric
addition of ketone 1a to nitro-olefin 2a
Based on our research interest in asymmetric catalysis,10 we
recently found that acyclic aliphatic amino acids and small
peptides mediate asymmetric intermolecular C–C bond forming
reactions with high stereoselectivity.11 These results made us
interested in whether chiral primary amines derived from acyclic
amino acids would be able to catalyze the asymmetric addition of
unmodified ketones to nitro-olefins (eqn (1)). Moreover, the high
modularity of the primary amines should increase the plausibility
of finding novel catalysts for this important C–C bond-forming
reaction.
Entry
Catalyst
Time/h
Yield (%)a
Drb
Ee (%)c
1
2
3
4
5
6
7
8
4
5
6
7
8
9
10
11
12
13
14
15
16
16
16
16
30
42
24
24
22
168
23
48
60
33
62
25
21
11
11
15
20 : 1
17 : 1
14 : 1
14 : 1
10 : 1
5 : 1
59
57
46
51
63
85
87
91
86
n.d.
91
89
b
(1)
We initially screened a library of simple amino acid derived
catalysts with a catalytic primary amine residue (30 mol%) for the
reaction between cyclohexanone 1a (0.75 mmol) and nitro-olefin
n.d.
14 : 1
10 : 1
n.d.
35 : 1
4 : 1
9
31
trace
13
10
11
12
a
21d
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm
University, Sweden. E-mail: acordova1a@netscape.net;
acordova@organ.su.se; Fax: +46 8 154908; Tel: +46 8 162479
{ Electronic supplementary information (ESI) available: Experimental
procedures. See DOI: 10.1039/b514783m
Isolated yield after silica-gel column chromatography. Syn : anti
c
ratio as determined by NMR analyses. Determined by chiral-phase
d
HPLC analyses. 15 mol% p-TsOH?H2O was added.
460 | Chem. Commun., 2006, 460–462
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Table 2 The primary amine 11-catalyzed direct enantioselective additions of cyclohexanone 1a to nitro-olefin 2a
Entry
Solvent
Additive (15 mol%)
Temp/uC
Time/h
Yield (%)a
Drb
Ee (%)c
1
2
3
4
5
6
7
9
10
11
12
13
14
15
a
DMSO
DMSO
DMSO
DMSO
DMSO
CHCl3
NMP
NMP
NMP
NMPh
NMP : DMSO (9 : 1)
NMP : DMSO (1 : 1)
NMP : DMSO (1 : 1)
—
rt
rt
rt
rt
rt
rt
rt
rt
rt
24
48
41
46
47
240
44
72
45
46h
96
72
48
42
15
37
29
36
37
18
64
92
14 : 1
9 : 1
11 : 1
14 : 1
12 : 1
5 : 1
25 : 1
27 : 1
19 : 1
14 : 1h
34 : 1
12 : 1
—
91
98
86
77
98
44
90
93
92
93h
96
96
—
77
TsOHd
AcOH
NBAe
DNBSAf
TsOH
—
TsOH
TsOHg
TsOHh
—
TsOH
TsOHi
TsOHg
b
87
90h
66
4
rt
rt
rt
65
trace
62
j
[bmin]PF6
5 : 1
c
Isolated yield after silica-gel column chromatography. Syn : anti ratio as determined by NMR analyses. Determined by chiral-phase
d
e
f
g
h
HPLC analyses. TsOH = p-TsOH?H2O. NBA = p-nitrobenzoic acid. DNBSA = 2,4-dinitrobenzosulfonic acid. 6 mol% TSOH. 0.5 M
i
2a. 30 mol% TSOH. [bmin]PF6 = 1-n-butyl-3-methylimidazoliumhexafluorophosphate.
j
found that the amino acid derived amides were more efficient than
the corresponding diamines under the set reaction conditions.
Encouraged by these initial results, we selected catalyst 11 for
further studies of the direct asymmetric addition of ketone 1a to
nitro-olefin 2a (Table 2).
and low to good enantioselectivity. For example, nitro-ketone 3i
was isolated as a single regioisomer in 83% yield with 27% ee.
The observed syn-diatereoselectivity and the absolute configu-
ration of the nitro-ketone products was explained by the plausible
transition state I where the Si-face of the nitro-olefin was
approached by the Re-face of the catalytically generated chiral
enamine. (Fig. 1).13
We found that the addition of a small amount of a Brønsted
acid (6–15 mol%) together with the H2O (5–10 equiv.) accelerated
the chiral amine 11-catalyzed asymmetric conjugate reactions. In
this context, catalyst 11 mediated the asymmetric assembly of 3a in
up to 98% ee in the presence of a small amount of p-toluene
sulfonic acid (p-TsOH, 15 mol%) or dinitrobenzosulfonic acid
(DNBSA, 15 mol%). To our delight, performing the asymmetric
conjugate additions in NMP (N-methylpyrrolidinone) significantly
increased the yield and diastereoselectivity of the reactions without
affecting the enantioselectivity.12 For example, alanine amide 11
catalyzed the asymmetric formation of 3a in 92% yield with 27 :
1 dr and 93% ee in NMP (Entry 9). Moreover, utilizing a 9 to 1
solvent mixture of NMP and DMSO further improved the
diastereo- and enantioselectivity. For instance, primary amine 11
mediated the formation of 3a in 66% yield with 34 : 1 dr and
96% ee under these reaction conditions (Entry 12). Decreasing the
catalyst to acid additive ratio from 5 : 1 to a 1 : 1 ratio completely
inhibited the Michael additions. Thus, catalyst 11 was deactivated
by protonation of the nucleophilic primary amine component. The
primary amines also catalyze the Michael reactions in ionic liquid
media, which allows for the recycling of the catalysts. We next
probed the alanine amide 11-catalyzed asymmetric reactions with a
set of ketones and nitro-olefins (Table 3).
The increased enantioselectivity by the addition of a small
amount of water and Brønsted acid may be explained by a
synergistic stabilization of transition state I by formation of a
charge-relay system. In addition, the water and acid plausibly
accelerate the reaction by facilitating the inter-conversion of the
different intermediates of the catalytic enamine cycle.14
In summary, we have demonstrated for the first time that simple
primary amino acid derivatives can catalyze the direct asymmetric
addition of ketones to nitro-olefins with high regio- diastereo- and
enantioselectivities. The high modularity of the catalysts together
with their simple preparation enables great possibilities in finding
novel selective organocatalysts for stereoselective Michael reactions
by combinatorial methods. Further expansion of the use of non-
toxic and inexpensive linear amino acid amides and their
derivatives in environmentally benign organocatalytic asymmetric
C–C bond-forming reactions, mechanistic studies and density
functional theory calculations are ongoing.
We gratefully acknowledge the Swedish National Research
Council, Carl-Trygger Foundation, Lars-Hierta Foundation and
Wenner-Gren Foundation for financial support.
The (S)-alanine amide 11-catalyzed the asymmetric additions of
ketones 1a–1e to nitro-olefins 2 with high diastereo- and
enantioselectivity to furnish the corresponding nitro-ketone
products 3a–3h in high yield with up to >38 : 1 dr and 99% ee.
In particular, the reactions with cyclic ketones as nucleophiles gave
excellent diastereo- and enantioselectivity. For instance, c-nitro-
ketone 3b was furnished in 75% yield with 23 : 1 dr and 98% ee.
The primary amine-catalyzed asymmetric additions with non-
symmetric acyclic ketones proceed with excellent regioselectivity
Fig. 1 Plausible transition state I for the primary amino acid amide-
catalyzed asymmetric additions of ketones to nitro-olefins.
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Table 3 Examples of different 11-catalyzed direct asymmetric addi-
tions of ketones to nitro-olefinsa
Notes and references
1 P. Perlmutter, Conjugate Addition Reactions in Organic Synthesis,
Pergamon, Oxford, 1992.
2 Reviews see: (a) K. Tomioka, Y. Nagaoka and M. Yamaguchi, in
Comprehensive Asymmetric Catalysis, ed. E. N. Jacobsen, A. Pfaltz and
H. Yamamoto, Springer, New York, 1999, vol. III, ch. 31.1 and 31.2,
pp. 1105–1139; (b) O. M. Berner, L. Tedeschi and D. Enders, Eur. J.
Org. Chem., 2002, 1877; (c) N. Krause and A. Hoffmann-Ro¨der,
Synthesis, 2001, 171; (d) J. Christoffers and A. Baro, Angew. Chem., Int.
Ed., 2003, 42, 1688.
Yield
Ee
Entry Ketone R
Product
Condition (%)b Drc (%)d
3 (a) P. I. Dalko and L. Moisan, Angew. Chem., Int. Ed., 2001, 40, 3726;
(b) B. List, Tetrahedron, 2002, 58, 5573; (c) R. O. Duthaler, Angew.
Chem., Int. Ed., 2003, 42, 975; (d) P. I. Dalko and L. Moisan, Angew.
Chem., Int. Ed., 2004, 116, 5248; (e) S. J. Miller, Acc. Chem. Res., 2004,
37, 601; (f) A. Berkessel, Curr. Opin. Chem. Biol., 2003, 7, 409; (g)
E. J. Jarvo and S. J. Miller, Tetrahedron, 2002, 58, 2481.
1
2
1a
1a
Ph
Naphtyl
3a
B
A
92
75
27 : 1 93
23 : 1 98
4 (a) S. Hannesian and V. Pham, Org. Lett., 2000, 2, 3737; (b) B. List,
P. Porjarliev and H. J. Martin, Org. Lett., 2001, 3, 2423; (c) D. Enders
and A. Seki, Synlett, 2002, 26.
3
4
5
1a
1a
4-MeOC6H4
4-NO2C6H4
Ph
B
82
82
19 : 1 90
5 H. J. Martin and B. List, Synlett, 2003, 1901.
6 (a) J. M. Betancort and C. F. Barbas III, Org. Lett., 2001, 3, 3737; (b)
J. M. Betancort, K. Sakthivel, R. Thayumanavan and C. F. Barbas III,
Tetrahedron Lett., 2001, 42, 4441; (c) J. M. Betancort, K. Sakthivel,
R. Thayumanavan, F. Tanaka and C. F. Barbas III, Synthesis, 2004,
1509; (d) D. Terakado, M. Takano and T. Oriyama, Chem. Lett., 2005,
34, 962; (e) A. Alexakis and O. Andrey, Org. Lett., 2002, 4, 3611; (f)
O. Andrey, A. Alexakis and G. Bernardinelli, Org. Lett., 2003, 5, 2559;
(g) O. Andrey, A. Alexakis, A. Tomassini and G. Bernardinelli, Adv.
Synth. Catal., 2004, 346, 1147; (h) T. Ishii, S. Fujioka, Y. Sekiguchi and
H. Kotsuki, J. Am. Chem. Soc., 2004, 126, 9558; (i) W. Wang, J. Wang
and H. Li, Angew. Chem., Int. Ed., 2005, 44, 1369; (j) Y. Hayashi,
H. Gotoh, T. Hayashi and M. Shoji, Angew. Chem., Int. Ed., 2005, 44,
4212.
Be
34 : 1 96
A
68 .28 : 1 95
7 For the use of chiral pyrrolidine tetrazoles see: A. J. A. Cobb,
D. A. Longbottom, D. M. Shaw and S. V. Ley, Chem. Commun., 2004,
1808; A. J. A. Cobb, D. M. Shaw, D. A. Longbottom, J. B. Gold and
S. V. Ley, Org. Biomol. Chem., 2005, 3, 84; C. E. T. Mitchell, A. J.
A. Cobb and S. Ley, Synlett, 2005, 4, 611.
8 For other organocatalytic Michael reactions see: N. A. Paras and D. W.
C. MacMillan, J. Am. Chem. Soc., 2001, 123, 4370; M. T.
Hechavarria Fonseca and B. List, Angew. Chem., Int. Ed., 2004, 43,
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67, 8331; N. Halland, P. S. Aburel and K. A. Jørgensen, Angew. Chem.,
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L. Deng, J. Am. Chem. Soc., 2004, 126, 9906.
6
7
Ph
Ph
B
45
45
5 : 1 67
A
38 : 1 99
9 For examples of the use of urea derivatives as catalysts in Michael
reactions with nitro-olefins see: T. Okino, Y. Hoashi and Y. Takemoto,
J. Am. Chem. Soc., 2003, 125, 12672; T. Okino, Y. Hoashi,
T. Furukawa, X. Xu and Y. Takemoto, J. Am. Chem. Soc., 2005,
127, 119.
8
9
1d
Ph
Ph
3g
B
A
63 .38 : 1 98
72
31 : 1 90
10 A. Co´rdova, M. Engqvist, I. Ibrahem, J. Casas and H. Sunde´n, Chem.
Commun., 2005, 2047; J. Casas, M. Engqvist, I. Ibrahem, B. Kaynak
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I. Ibrahem, L. Eriksson and A. Co´rdova, Angew. Chem., Int. Ed., 2005,
44, 6532 and references therein.
10
Ph
Be
83
1 : 2 27
11 (a) A. Co´rdova, W. Zou, I. Ibrahem, E. Reyes, M. Engqvist and
W.-W. Liao, Chem. Commun., 2005, 3586; (b) W. Zou, I. Ibrahem,
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Eur. J., 2005, 11, 7025; (d) Y. Xu, W. Zou, H. Sunde´n and I. Ibrahem,
Manuscript.
12 The chiral amines also catalyzed the reactions in CH3CN, THF and
DMF.
13 D. Seebach and J. Golinski, Helv. Chim. Acta, 1981, 64, 1413;
D. Seebach, M. Missbach, G. Calderari and M. Eberle, J. Am. Chem.
Soc., 1990, 112, 7625 and references therein.
a
A = To a suspension of 11 (30 mol%) in NMP : DMSO, 9 : 1
(1 mL) and H2O (45mL, 10 equiv.) was added ketone 1 (0.75 mmol)
and nitro-olefin 2 (0.25 mmol). B = The same as A but p-TsOH
b
(15 mol%) was also added and the solvent was NMP. Isolated
yield after silica-gel column chromatography. Syn : anti ratio as
c
d
determined by NMR analyses. Determined by chiral-phase HPLC
e
14 Brønsted acids also accelerate the chiral pyrrolidine-catalyzed conjugate
addition of ketones to nitro-olefins, see ref. 6.
analyses. Reaction performed at 4 uC.
462 | Chem. Commun., 2006, 460–462
This journal is ß The Royal Society of Chemistry 2006