Peptide-catalyzed stereoselective conjugate addition reactions generating all-carbon quaternary stereogenic Centers

Article abstract of DOI:10.1002/anie.201301583

A powerful catalyst: Quaternary stereogenic centers adjacent to tertiary stereocenters were formed with high diastereoselectivities and enantioselectivities in conjugate addition reactions between aldehydes and β,β-disubstituted nitroolefins by using a peptidic catalyst (see scheme). γ-Amino acids and heterocyclic compounds bearing quaternary stereogenic centers are easily accessible from the products. Copyright

Full text of DOI:10.1002/anie.201301583

Angewandte
Chemie
Communications
Asymmetric Catalysis
R. Kastl, H. Wennemers*
&&&& — &&&&
Peptide-Catalyzed Stereoselective
Conjugate Addition Reactions Generating
All-Carbon Quaternary Stereogenic
Centers
A powerful catalyst: Quaternary stereo-
genic centers adjacent to tertiary stereo-
centers were formed with high diastereo-
selectivities and enantioselectivities in
conjugate addition reactions between
aldehydes and b,b-disubstituted nitro-
olefins by using a peptidic catalyst (see
scheme). g-Amino acids and heterocyclic
compounds bearing quaternary stereo-
genic centers are easily accessible from
the products.
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
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DOI: 10.1002/anie.201301583
Asymmetric Catalysis
Peptide-Catalyzed Stereoselective Conjugate Addition Reactions
Generating All-Carbon Quaternary Stereogenic Centers**
Robert Kastl and Helma Wennemers*
Dedicated to Professor Jack Dunitz on the occasion of his 90th birthday
Stereoselective conjugate addition reactions of carbon-based
nucleophiles are among the most useful synthetic trans-
Herein we present a peptide as an effective stereoselective
catalyst for asymmetric conjugate addition reactions of
aldehydes to b,b-disubstituted nitroolefins. We also demon-
strate that the resulting g-nitroaldehydes can be readily
converted into other valuable compounds with quaternary
stereogenic centers such as chiral pyrrolidines, g-amino acids,
or g-butyrolactones.
formations.[1] Particularly challenging are C C bond forming
À
reactions that afford acyclic compounds with an all-carbon
quaternary stereogenic center under mild organocatalytic
conditions.[2–4] Among the few examples are mainly reactions
in which the quaternary stereogenic center is derived from
substituted 1,3-dicarbonyl compounds or a,a-disubstituted
aldehydes that act as nucleophiles upon activation by
a catalyst.[3] Reactions in which the quaternary stereogenic
center is derived from the electrophile are even less
common.[4,5] In the past decade, impressive progress has
been made in the development of catalysts for stereoselective
reactions between aldehydes and nitroolefins to provide
synthetically valuable g-nitroaldehydes.[6–13] The most com-
monly used Michael acceptors are b-monosubstituted nitro-
olefins (Scheme 1, top),[6–9] but also nitroethylene[10,11] and
Previously our group introduced tripeptides of the type
Pro-Pro-Xaa (Xaa = acidic amino acid) as highly reactive and
stereoselective catalysts for aldol reactions and conjugate
addition reactions of aldehydes to nitroolefins.[9,10,12,14] For
example, H-d-Pro-Pro-Glu-NH2 (1a) and H-Pro-Pro-d-Gln-
OH catalyze conjugate addition reactions of aldehydes with
b-monosubstituted nitroolefins and a,b-disubstituted nitro-
olefins, respectively.[9,12] Products resulting from homo-aldol
reactions that are typical side products in such conjugate
addition reactions form either not at all or only in minimal
amounts despite the fact that the related peptide H-Pro-Pro-
Asp-NH2 is a very good catalyst for aldol reactions.[14] Thus,
the modular nature of these peptidic catalysts allows for fine-
tuning and optimizing their structural and functional proper-
ties to the desired reaction pathway and to accommodate the
requirements of a given substrate combination. These fea-
tures suggest that a member of the class of peptides Pro-Pro-
Xaa might also fulfill the requirements for catalyzing
stereoselective addition reactions between aldehydes and
b,b-disubstituted nitroolefins.
Scheme 1. Conjugate addition reactions between aldehydes and nitro-
We started our investigations by exploring the catalytic
properties of peptides of the type Pro-Pro-Xaa in the reaction
of butanal with (Z)-ethyl 2-(4-fluorophenyl)-3-nitroacrylate
(2a). All reactions were performed with the trifluoroacetic
acid (TFA) salts of the peptides, the equivalent amount of N-
methylmorpholine (NMM) and 2 equivalents of the aldehyde
with respect to the nitroolefin. Despite the electron-with-
drawing and therefore activating substituents, b,b-disubsti-
tuted nitroolefin 2a proved to be significantly less prone to
form conjugate addition products with aldehydes than b-
monosubstituted nitroolefins. Whereas b-nitroolefins react
readily with aldehydes in the presence of as little as ꢀ 1 mol%
of H-d-Pro-Pro-Glu-NH2 (1a) in a mixture of CHCl3 and
iPrOH,[9] only a small amount of the b,b-disubstituted nitro-
olefin 2a (ꢀ 10%) was converted to the desired addition
product 3a in the presence of 10 mol% of 1a within three
days under the same reaction conditions (Table 1, entry 1).
Instead, a significant amount of the homo-aldol reaction
product formed. Reassuringly, the desired g-nitroaldehyde 3a
was obtained in good stereoselectivity (d.r. 6.4:1, 86% ee,
Table 1, entry 1). A higher conversion to the product was
olefins.
a,b-disubstituted nitroolefins[12,13] have been reacted with
aldehydes in the presence of chiral amine-based catalysts. In
contrast, reactions with b,b-disubstituted nitroolefins to
provide g-nitroaldehydes with an all-carbon quaternary
stereogenic center adjacent to a tertiary stereocenter have
so far not been realized (Scheme 1, bottom).
[*] R. Kastl, Prof. Dr. H. Wennemers
ETH Zꢀrich, Laboratorium fꢀr Organische Chemie
Department Chemie und Angewandte Biowissenschaften
Wolfgang Pauli-Strasse 10, 8093 Zꢀrich (Switzerland)
E-mail: helma.wennemers@org.chem.ethz.ch
Homepage: http://www.wennemers.ethz.ch
[**] We thank the Swiss National Science Foundation and Bachem for
financial support. We thank M. Neuburger for recording the X-ray
crystal structure. We are also grateful to Basel University, where part
of this research was carried out.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201301583.
2
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Chemie
Table 1: 1,4-Addition reactions between butanal and nitroolefin 2a
catalyzed by peptides of the type H-d-Pro-Pro-Xaa.
Catalyst 1g is a 1:1 mixture of the two diastereoisomers H-
d-Pro-Pro-NH-(R)-CH(Ph)CH2-4-Me-C6H4 (1g-R) and H-d-
Pro-Pro-NH-(S)-CH(Ph)CH2-4-Me-C6H4 (1g-S). Evaluation
of the catalytic performance of the individual stereoisomers
1g-R and 1g-S showed that their reactivities and in particular
stereoselectivities differ only slightly from those of the
mixture (Table 1, entry 14–16). Since racemic 1-phenyl-2-(p-
tolyl)ethylamine is more readily available than the enantio-
merically pure amines needed for the synthesis of 1g-R and
1g-S, all further studies were performed with the mixture of
the two diastereoisomers.
Entry Catalyst R1
R2
Solvent Conv. d.r.[a] ee
[%][a]
[%][b]
1
1a
CONH2 CH2CO2H
CHCl3/ <10 6.4:1 86
iPrOH
9:1
Table 2: Scope of 1,4-addition reactions between aldehydes and b,b-
disubstituted nitroolefins.
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1a
1b
1c
1d
1e
1 f
CONH2 CH2CO2H
iPrOH
iPrOH
iPrOH
50
51
72
79
86
86
78
4.0:1 75
4.0:1 77
4.3:1 80
4.2:1 80
3.6:1 80
4:7:1 85
4.6:1 90
1.1:1 nd[d]
3.0:1 81
4:8:1 92
5.0:1 93
6.1:1 89
6.0:1 94
5.6:1 95
6.0:1 93
H
H
H
CH2CO2H
CH2CO2Me
(CH2)2CO2Me iPrOH
CO2Me (CH2)2CO2Me iPrOH
CO2Me Ph
iPrOH
iPrOH
MeOH 10
EtOH
CHCl3
toluene 21
THF 27
tBuOH 96
tBuOH 98
tBuOH 86
1g[c]
1g[c]
1g[c]
1g[c]
1g[c]
1g[c]
1g[c]
1g-R[e]
1g-S[e]
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
33
36
Entry
1
Product
Yield [%][a]
82
d.r.[b]
6.0:1
ee [%][c]
3a
3b
3c
3d
3e
3 f
3g
94
2
3
4
5
6
7
85
84
85
83
90
72
5.0:1
5.5:1
5.5:1
6.5:1
6.5:1
6.0:1
94
94
96
91
94
94
[a] Determined by 1H NMR spectroscopy of the crude reaction mixture.
[b] Determined by chiral-stationary-phase HPLC analysis. [c] Diastereo-
isomeric mixture with (R)- and (S)-configured C-terminal moiety. [d] Not
determined. [e] Enantiomerically pure 1g with either (R)- or (S)-
configured C-terminal moieties.
observed when merely iPrOH was used as solvent although at
the expense of the stereoselectivity (Table 1, entry 2). Varia-
tions in the catalyst structure revealed that the d-Pro-l-Pro
motif is optimal for high stereoselectivities (see the Support-
ing Information for details). More importantly, the functional
group at the C-terminal end was found to affect the reactivity
and chemoselectivity (aldol versus conjugate addition reac-
tions) of the peptidic catalysts significantly. The highest
conversions to the conjugate addition product 3a were
achieved with peptides bearing a methylester and/or aromatic
residues instead of a carboxylic acid at the C terminus
(Table 1, entries 4–8). This is remarkable, since the presence
of a carboxylic acid moiety within the peptidic catalyst had
been found to provide highest reactivity and stereoselectivity
in the previously examined peptide-catalyzed conjugate
addition reactions.[9b,15] The best catalyst with respect to
stereoselectivity and reactivity was found to be peptide H-d-
Pro-Pro-NHCH(Ph)CH2-4-Me-C6H4 (1g) with two aromatic
residues at the C terminus (Table 1, entry 8). Further opti-
mization of the reaction parameters showed that tBuOH is
the best solvent (Table 1, entries 8–14). Under these opti-
mized conditions nitroolefin 2a reacted quantitatively to the
conjugate addition product 3a, which was obtained with
a diastereoselectivity of 6:1 and an enantioselectivity of 94%
ee (Table 1, entry 14).
8
3h
3i
88
83
85
87
5.5:1
3.0:1
89
95
95
97
9
10
11
3j
6.5:1
3k
10.0:1
12
3l
85
4.5:1
91
[a] Yields correspond to g-nitroaldehydes isolated as a mixture of
stereoisomers after 48–72 h. [b] Determined by 1H NMR spectroscopy of
the crude reaction mixture. [c] Determined by chiral-stationary-phase
HPLC analysis.
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With the optimized reaction conditions defined we
explored the scope of the peptide-catalyzed conjugate
addition reactions and allowed a range of different aldehyde
and b,b-disubstituted nitroolefin combinations to react with
each other in the presence of 10 mol% of peptide 1g. The
desired g-nitroaldehydes 3a–3l bearing an all-carbon quater-
nary stereogenic center adjacent to a tertiary stereocenter
were obtained in good yields and stereoselectivities (Table 2).
The best results with respect to the diastereoselectivity (10:1)
and enantioselectivity (97% ee) were achieved when using
electron-poor aromatic b,b-disubstituted nitroolefins (e.g.
Table 2, entry 11); however, good product yields and stereo-
selectivities were also obtained with nitroacrylates bearing
electron-rich aromatic substituents (e.g. Table 2, entries 7 and
8). Also aldehydes bearing functional groups such as esters
reacted readily with the b,b-disubstituted nitroolefins
(Table 2, entry 12). Current limitations are aliphatic nitro-
acrylates,[16] b,b-nitroolefins lacking an additional electron-
withdrawing group, and a- or b-branched aldehydes that did
not react or only in trace amounts to the desired g-nitro-
aldehyde.
(Scheme 2b). Crystals suitable for X-ray crystal structure
analysis of lactone 5 were obtained from Et2O/pentane. The
crystal structure confirmed the relative configuration and
allowed to determine the absolute configuration of both
stereogenic centers within the parent g-nitroaldehyde to be S.
Aside from the pyrrolidines and lactones, also 2,3,3-trisub-
stituted g-amino acid 6 was readily prepared (Scheme 2c).
Towards this goal g-nitroaldehyde 3a was transformed to
Fmoc-protected g2,3,3-amino acid 6 in five steps by following
a previously established procedure.[12] Such amino acids with
an all-carbon quaternary stereogenic center next to a tertiary
stereocenter have to our knowledge not been prepared to
date and might not only be interesting for the development of
therapeutics but also for foldamer research.[17,18]
Previous studies on the mechanism of conjugate addition
reactions between aldehydes and nitroolefins had shown that
catalysts bearing an appropriately positioned proton donor do
not require any additives for high reactivity and stereoselec-
tivity, whereas an acidic cocatalyst is critical for catalysts
lacking an intramolecular proton donor.[15,20] Thus, for the
herein
presented
peptidic
catalyst
H-d-Pro-Pro-
Next, we explored the synthetic versatility of the g-
nitroaldehydes for the preparation of g-amino acids as well as
heterocyclic compounds with all-carbon quaternary stereo-
genic centers that are valuable for the synthesis of therapeuti-
cally active compounds.[17] These studies also allowed for the
unambiguous determination of the relative and absolute
configuration of the major stereoisomer formed in the
peptide-catalyzed addition reactions. For example, N-tosy-
lated pyrrolidine 4 was obtained by reductive amination of g-
nitroaldehyde 3a followed by tosylation (Scheme 2a). NMR-
spectroscopic analysis including NOE spectroscopy of 4
NHCH(Ph)CH2-4-Me-C6H4 (1g) the presence of an addi-
tional acid was expected to be important. Studies in which the
acidic cocatalyst was varied showed that this is indeed the
case. Best results with respect to reactivity and stereoselec-
tivity were obtained when the trifluoroacetic acid (TFA) salt
of the peptide and an equivalent amount of N-methylmor-
pholine (NMM) were used.[21] Significantly lower reaction
rates were observed when the peptide was used in the absence
of any acidic additive.[21] The question why a peptidic catalyst
lacking an intramolecular carboxylic acid moiety is better
suited for the present reaction compared to peptides bearing
a proton donor that had been found to be optimal for related
reactions is not trivial. The findings suggest that steric
shielding and/or interaction between the aromatic portion
of catalyst 1g and the b,b-disubstituted nitroolefin are critical
for favoring the desired conjugate addition over the compet-
ing aldol reaction. Detailed NMR-spectroscopic and kinetic
studies that will shed more light on the mechanism of the
presented peptide-catalyzed reaction are currently ongoing
and will be reported in due course.
In summary, we have shown that the peptide H-d-Pro-
Pro-NHCH(Ph)CH2-4-Me-C6H4 (1g) is a powerful catalyst
for conjugate addition reactions of aldehydes to b,b-disub-
stituted nitroolefins to afford synthetically versatile g-nitro-
aldehydes with an all-carbon quaternary stereogenic center
adjacent to a tertiary stereocenter in high yields and
stereoselectivities. The g-nitroaldehydes were obtained with
high chemoselectivity over competing homo-aldol products
and provide easy access to novel g2,3,3-amino acids, g-
butyrolactones, and chiral pyrrolidines bearing all-carbon
quaternary stereogenic centers.
Scheme 2. Synthesis of pyrrolidine 4, lactone 5, g-amino acid 6, and
the crystal structure of lactone 5.[19]
supports, as expected from the related reactions with b- and
a,b-substituted nitroolefins, the relative syn configuration of
the ethyl group and the aromatic moiety within 3 (anti within
4, see the Supporting Information for details). Reduction of
the aldehyde moiety within g-nitroaldehyde 3c using NaBH4
yielded after intramolecular cyclisation of the initially formed
hydroxyester the crystalline g-butyrolactone 5 in 95% yield
Experimental Section
General procedure for the conjugate addition reactions: The nitro-
olefin (0.42 mmol, 1 equiv) was added to a solution of the peptide (as
the TFA salt, 42 mmol, 10 mol%), NMM (42 mmol, 10 mol%), and the
aldehyde (0.84 mmol, 2 equiv) in tert-BuOH (1 mL). The reaction
4
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mixture was agitated at room temperature for 48–72 h, and then all
volatile components were removed at reduced pressure. The resulting
crude product was purified by flash column chromatography on silica
gel by using a mixture of pentanes and EtOAc as eluent to afford g-
nitroaldehydes 3.
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Received: February 23, 2013
Published online: && &&, &&&&
Keywords: 1,4-addition reactions · g-amino acids ·
.
asymmetric catalysis · nitroolefins · peptides
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[19] CCDC-897771 (5) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
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[21] For example, with acetic acid or p-nitrophenol as additives 80%
and 70% conversion to the product within 48 h and 96 h,
respectively, and in both cases stereoselectivities of 3.5:1 (syn/
anti) and 93% ee were observed. In the absence of an additive,
9 days were necessary to achieve > 90% conversion to the
product with a d.r. of 2.5:1 and 92% ee.
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These are not the final page numbers!