Small peptide-catalyzed enantioselective addition of ketones to nitroolefins

Article abstract of DOI:10.1002/adsc.200505373

The direct small peptide-catalyzed enantioselective Michael addition of ketones to nitroolefins is presented. Simple di- and tripeptides derived from alanine catalyze the asymmetric Michael additions with high stereoselectivity and furnish the correspondi

Full text of DOI:10.1002/adsc.200505373

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DOI: 10.1002/adsc.200505373
Small Peptide-Catalyzed Enantioselective Addition of Ketones to
Nitroolefins
´
´
Yongmei Xu, Weibiao Zou, Henrik Sunden, Ismail Ibrahem, Armando Cordova*
Department ofOrganic Chemistry, Arrhenius Laboratory, Stockholm University, 106 91 Stockholm, Sweden
Fax: (þ46)-8-154-908, e-mail: acordova@organ.su.se
Received: September 26, 2005; Accepted: December 22, 2005
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: The direct small peptide-catalyzed enan-
tioselective Michael addition ofketones to nitroole-
fins is presented. Simple di- and tripeptides derived
from alanine catalyze the asymmetric Michael addi-
tions with high stereoselectivity and furnish the cor-
responding Michael products in high yield with up
to 68:1 dr and 98% ee. The study demonstrates
that small, readily prepared peptides with increased
structural complexity as compared to the parent ami-
no acid mediate the asymmetric Michael reaction
with superior reactivity and enantioselectivity.
they are generally more complex and prepared in
more steps than a simple amino acid or peptide catalysts.
Herein, we present that simple dipeptides with a catalyt-
ic primary amine residue catalyze the direct asymmetric
Michael addition ofketones to nitrooleifns with high
stereoselectivity and furnish the corresponding g-nitro
ketones with up to 68:1 dr and 98% ee.
Based on our research interest in asymmetric cataly-
sis,[17] we recently found that acyclic aliphatic amino
acids catalyze asymmetric intermolecular aldol reac-
tions and Mannich reactions with high stereoselectivi-
ties.[18] The lessons from these studies made us interested
in whether acyclic amino acids as well as small peptides
derived from them could react with a ketone and form a
catalytic chiral enamine, which could serve as a nucleo-
phile in Michael additions to nitroolefins [Eq. (1)]. We
expected that addition ofa small excess ofwater would
increase the efficiency and circumvent the need of add-
Keywords: asymmetric catalysis; ketones; Michael
reaction; nitroolefins; peptides
The Michael addition is a fundamental carbon-carbon ing an acidic additive. In addition, water would facilitate
bond-forming reaction in organic synthesis.[1] Therefore, hydrogen bonding and proton transfer, which could
chemists have developed several catalytic asymmetric plausibly improve the enantioselectivity ofthe Michael
protocols for this important reaction.[2] In recent years, reaction.
an intense research effort has been made to find non-
toxic chiral organic molecules as catalysts for enantiose-
lective reactions.[3] For example, Miller[4] and Jacobsen[5]
have employed catalytic peptides and peptide-like mol-
ecules as catalysts for asymmetric additions. Their struc-
tural diversity, availability and modularity could make
ð1Þ
them ideal asymmetric organocatalysts for a variety of
transformations.[6] Proline[7] and N-terminal prolylpep-
tides[8] have been described as catalysts for the asymmet- In an initial catalyst screen ofthe reaction between cy-
ric Michael reaction. However, only moderate enantio- clohexanone 1a and nitroolefin 2a in wet DMSO, we
selectivity is typically obtained. For example, proline found that acyclic primary amino acids catalyzed the
and N-terminal prolyldipeptides catalyze the asymmet- asymmetric formation of Michael product (R, S)-3a in
ric formation of g-nitroketones with 5–76% ee and 0– low yields (7–21%) and moderate to good ees (44–
31% ee, respectively. Proline-derived derivatives have 81%) (Table 1). The low yields were due to competing
been proven to be more succesful for the asymmetric polymerization ofthe nitroolefin.
Michael reaction.[9–12] Recently, Alexakis,[13] Kotsuki,[14]
To our delight the N-terminal alanyldi- and tri-pep-
Wang[15] and Hayashi[16] reported excellent highly enan- tides were more efficient as compared to the primary
tioselective Michael conjugate additions that were cata- amino acids at room temperature and furnished Michael
lyzed by chiral pyrrolidine-based catalysts. However, product (R,S)-3a in higher yields (40–58%), diastereo-
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Small Peptide-Catalyzed Enantioselective Addition ofKetones to Nitrooleifns
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Table 1. Catalyst screen.[a]
[a]
To a suspension ofcatalyst (30 mol %) in DMSO (1 mL), and H O (45 mL, 10 equivs.)
2
were added ketone 1a (0.75 mmol) and nitroolefin 2a (0.25 mmol) and the resulting re-
action mixture was stirred for the time and at the temperature shown in the table.
Isolated yield ofpure product 3a.
dr (syn :anti) as determined by NMR analyses.
Determined by chiral-phase HPLC analyses.
[b]
[c]
[d]
[e]
[f]
Reaction performed in a DMSO:NMP-1: 1 mixture.
Reaction performed in a DMSO:NMP-1: 1 mixture with 45 mol % catalyst. NMP¼N-
methyl-2-pyrrolidinone, Abu¼(2S)-2-aminobutyric acid, Nva¼(S)-norvaline.
selectivities (6:1–24:1 dr) and ees (78–94%). Thus, in- ala-ala-OEt furnished 3a in 10% yield with 10:1 dr(syn:-
creased structural complexity provides superior reactiv- anti) and 78% ee after 9 days, which is more than 20
ity and stereoselectivity for the acyclic amino acid-cata- times slower than ala-ala. We found that the dipeptides
lyzed Michael reaction. In addition, the acid moiety of catalyze the Michael additions with best efficiency in
the dipeptide is important to achieve increased efficien- NMP and DMSO. The highest efficiency and stereose-
cy and asymmetric induction. For instance, the dipeptide lectivity was obtained when the ala-ala mediated reac-
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Yongmei Xu et al.
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Table 2. Examples ofoptimization experiments for the ( S)-ala-(S)-ala-, (S)-ala-(S)-phe-
and (S)-ala-(R)-ala-catalyzed Michael addititions.
[a]
To a suspension ofcatalyst (30 mol %) in solvent (1 mL), and H O (45 mL, 10 equivs.)
2
were added ketone 1a (0.75 mmol) and nitroolefin 2a (0.25 mmol) and the resulting re-
action mixture was stirred for the time and at the temperature shown in the table.
Isolated yield ofpure product 3a.
dr (syn :anti) as determined by NMR analyses.
Determined by chiral-phase HPLC analyses.
5 equivs. H2O.
20 equivs. H2O.
ala-phe used as the catalyst.
(S)-ala-(R)-ala used as the catalyst.
[b]
[c]
[d]
[e]
[f]
[g]
[h]
tions were performed in a wet (10–20 equivs. H2O) sol- or (S)-ala-(R)-ala-catalyzed reaction with a set ofke-
vent mixture ofDMSO: N-methyl-2-pyrrolidinone tones and nitroolefins (Table 3).
(NMP)-1:1 (Table 2).
The reaction was not efficient in CHCl3 due to the low additions with cyclic ketones 1a–d and 1f, g as the do-
solubility ofthe dipeptide catalyst. In addition, decreas- nors with excellent enantioselectivity and furnished
To our delight the dipeptides catalyzed the conjugate
ing the reaction temperature increased the stereoselec- the Michael products 3a–g and 3i, j in good yield with
tivity ofthe transof rmation. For example, ( S)-ala-(S)- 12:1–36:1 dr and 90–98% ee. For example, (S)-ala-
ala and (S)-ala-(R)-ala catalyzed the asymmetric forma- (R)-ala mediated the asymmetric formation of 3b in
tion of 3a with up to 93% and 97% ee, respectively, at 79% yield with 22:1 dr and 98% ee. Having an elec-
ꢀ208C (Table 2). The results demonstrated that chang- tron-withdrawing group at the aromatic moiety ofthe
ing the stereochemistry from (S) to (R) ofthe C-terminal
amino acid ofthe dipeptide improved the enantioselec-
tivity ofthe Michael addition. Encouraged by these re-
nitroolefin increased the reactivity. Moreover, the di-
peptides catalyze the Michael additions with protected
dihydroxyacetone 1d, which is an important donor in
sults, we next probed the scope ofthe ( S)-ala-(S)-ala- the de novo synthesis ofcarbohydrates, [19] to form 5-ni-
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Small Peptide-Catalyzed Enantioselective Addition ofKetones to Nitrooleifns
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Table 3. The (S)-ala-(S)-ala- and (S)-ala-(R)-ala-catalyzed direct enantioselective Mi-
chael additions ofketones to nitrooleifns.
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Yongmei Xu et al.
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Table 3. (Continued).
[a]
A¼To a suspension of( S)-ala-(S)-ala (30 mol %) in DMSO:NMP (1: 1) (1 mL), and
H2O (45 mL, 10 equivs.) were added ketone 1 (0.75 mmol) and nitroolefin 2
(0.25 mmol) and the resulting reaction mixture was stirred for 3 days at 4 8C. B ¼To
a suspension of( S)-ala-(R)-ala (45 mol %) in DMSO :NMP (1: 1) (1 mL), and H2O
(45 mL, 10 equivs.) were added ketone 1 (0.75 mmol) and nitroolefin 2 (0.25 mmol)
and the resulting reaction mixture was stirred for 3 days at ꢀ20 8C.
Isolated yield ofpure product 3a.
dr (syn :anti) as determined by NMR analyses.
Determined by chiral-phase HPLC analyses.
Same conditions as B but the reaction time was 48 h.
The combined yield of 3f and 3f’ (2: 1 ratio).
dr for both 3f and 3f’.
ee of 3f’.
Same conditions as A but reaction performed at ꢀ208C and run for 48 h.
Same conditions as B but reaction performed at 48C and run for 48 h.
Same conditions as B but 15 mol % catalyst.
[b]
[c]
[d]
[e]
[f]
[g]
[h]
[i]
[j]
[k]
[l]
Same conditions as A but reaction perfotmed at room temperature.
[m] ee ofthe anti-diastereoisomer.
tro-5-deoxy-5-aryl-5-deoxypentoses such as 3g with lization ofthe transition state, which is improved by a
high diastereo- and enantioselectivity (12:1 dr and small amount ofwater.
92% ee). The ala-ala-catalyzed Michael addition with
In summary, the direct, small peptide-catalyzed enan-
cyclopentanone gave the corresponding aldol product tioselective Michael addition ofketones to nitroolefins
3l in good enantiomeric excess (79% ee). The primary is presented. Simple di- and tripeptides derived from ala-
amino acids and dipeptides were also able to utilize acy- ninecatalyzethe asymmetric Michael additions with high
clic ketones and aldehydes as a donors. For example, ala- chemo- and stereoselectivity and furnish the correspond-
ala and (S)-ala-(R)-ala mediated the asymmetric forma- ing Michael products in high yield with up to 68:1 dr and
tion ofMichael products 3h and 3k with excellent regio- 98% ee. The study demonstrates that simple peptides
selectivity and moderate enantioselectivity (40% ee) withincreasedcomplexityascomparedtotheparentami-
and in 58% yield with 58% ee, respectively.
no acid mediate the Michael reaction with superior enan-
We believe that the dipeptide-catalyzed asymmetric tioselectivity and reactivity. Thus, readily prepared, high-
Michael reaction proceeds via a plausible catalytic en- ly modular peptides with a primary amine at the N-termi-
amine mechanism that is suggested in Figure 1. To ex- nus should be considered in the design and tuning ofnov-
plain the syn-diastereoselectivity and the absolute con- el inexpensive organocatalysts for the direct asymmetric
figuration observed, we propose transition state I based Michael reaction. In addition, small peptides and their
on Seebachꢁs model for the dipeptide-catalyzed asym- analogues are environmentally benign and non-toxic.
metric Michael additions.[20] The acid moiety and the Development ofnovel catalytic di- and tripeptide libra-
amide bond ofthe dipeptide plausibly assist in the stabi-
ries and mechanistic studies are ongoing.
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Small Peptide-Catalyzed Enantioselective Addition ofKetones to Nitrooleifns
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Figure 1. Plausible reaction mechanism and transition state I for the dipeptide-catalyzed asymmetric nitro-Michael reaction.
Experimental Section
New York, 1999, chap. 31.1 and 31.2, pp. 1105–1139;
General Procedure for the Conjugate Addition of a
Ketone to a Nitroolefin
b) O. M. Berner, L. Tedeschi, D. Enders, Eur. J. Org.
Chem. 2002, 1877; c) N. Krause, A. Hoffmann-Rçder,
Synthesis 2001, 171; d) J. Christoffers, A. Baro, Angew.
Chem. Int. Ed. 2003, 42, 1688.
To a suspension ofcatalyst (30 mol %) in DMSO (0.5 mL),
NMP (0.5 mL) and H2O (45 mL, 10 equivs.) were added the rel-
evant ketone (0.75 mmol) and nitroolefin (0.25 mmol). The re-
sulting mixture was stirred for the time and temperature given
in the tables. The reaction was quenched with brine and ex-
tracted with ethyl acetate (3ꢁ10 mL), the combined organic
phase was dried over anhydrous Na2SO4, filtered and concen-
trated under reduced pressure. The residue was purified by
flash column chromatography (silica gel/pentane:ethyl
acetate¼10:1–4:1) to give the Michael products. The ee of
the product was determined by chiral HPLC analysis. Relative
(syn) and absolute configuration of the product was deter-
mined by comparison with the known 1H NMR data and opti-
cal rotation values.
[3] Excellent reviews see: a) P. I. Dalko, L. Moisan, Angew.
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We gratefully acknowledge the Swedish National Research
Council, Carl-Trygger Foundation and Wenner-Gren-Founda-
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