Peptide catalyzed asymmetric conjugate addition reactions of aldehydes to nitroethylene - A convenient entry into γ2-amino acids

Article abstract of DOI:10.1021/ja801027s

The peptide H-d-Pro-Pro-Glu-NH₂ is a highly effective catalyst for conjugate addition reactions between aldehydes and nitroethylene. Only 1 mol % of H-d-Pro-Pro-Glu-NH₂ and a 1.5-fold excess of aldehyde with respect to nitroethylene suffice to obtain γ-nitroaldehydes and, after reduction, monosubstituted γ-nitroalcohols in excellent yields and optical purities. The products can be readily converted into γ²-amino acids, thereby opening an effective direct entry into this important class of compounds. Copyright

Full text of DOI:10.1021/ja801027s

Published on Web 04/04/2008
Peptide Catalyzed Asymmetric Conjugate Addition Reactions
of Aldehydes to Nitroethylene—A Convenient Entry into
γ2-Amino Acids
Markus Wiesner , Jefferson D. Revell , Sandro Tonazzi , and Helma Wennemers*
Department of Chemistry, UniVersity of Basel, St. Johanns-Ring 19, CH-4056 Basel, Switzerland
Received February 10, 2008; E-mail: helma.wennemers@unibas.ch
Table 1. 1,4-Addition Reactions between Dihydrocinnamaldehyde
and Nitroethylene Catalyzed by Peptides 1 and 2a
Asymmetric conjugate addition reactions of carbon-centered
nucleophiles are among the most useful and challenging
synthetic transformations.1 Over recent years, impressive progress
has been made on the development of asymmetric catalysts for
conjugate addition reactions of aldehydes to nitroolefins, af-
fording γ-nitroaldehydes as important synthetic intermediates.2–4
The most commonly used Michael acceptors thus far are
ꢀ-substituted nitroolefins, providing 2,3-disubstituted γ-nitroal-
dehydes. We became interested in employing nitroethylene as
a Michael acceptor since this would afford access to monosub-
stituted γ-nitroaldehydes (eq 1). These would allow for conver-
sion into monosubstituted γ2-amino acids as important building
blocks in the development of therapeutics or within foldamer
research.5,6 Common procedures for the synthesis of γ2-amino
acids rely on the use of chiral auxiliaries.7 A direct more efficient
route would thus facilitate their accessibility. Herein we present
a highly effective tripeptidic catalyst for asymmetric conjugate
addition reactions of aldehydes to nitroethylene. Only 1 mol %
of the catalyst is sufficient to achieve high enantioselectivities
and yields across a range of aliphatic and functionalized
aldehydes. The γ-nitroaldehydes were readily converted into
γ2-amino acids.
entry
cat.
equiv of RCHO
concb (M)
time (h)
convc (%)
eed (%)
1
2
3
4
5
6
7
1
2
2
2
2
2
1
3
3
3
1.5
1.5
1.5
1.5
0.5
0.5
30
10
10
15
15
15
50
70
90
95
90
g95
80
85
90
95
>95
>95
90
0.25
0.25
0.1
0.05
0.1
85
90
a Reactions were performed using the TFA salts of the peptidic
catalysts and the equivalent amount of N-methylmorpholine (NMM).
b Concentration of nitroethylene in the CHCl3 solution. c Conversion
estimated by 1H NMR spectroscopic analysis. d Determined by a 1H
NMR spectroscopic analysis using a chiral amine (ref 9; see Supporting
Information).
conversion, >95% ee) were obtained with 1 mol % of 2, a 1.5-
fold excess of aldehyde at a concentration of 0.1 M in
chloroform (Table 1, entry 5).10
Previously, we introduced the peptide H-D-Pro-Pro-Asp-NH2
1 as an efficient catalyst for conjugate addition reactions of
aldehydes to ꢀ-substituted nitroolefins.4,8 We therefore started
our investigations by testing whether 1 would also catalyze
asymmetric conjugate addition reactions of aldehydes to nitro-
ethylene. The reaction between nitroethylene and dihydrocin-
namaldehyde was used as a test reaction, and we were pleased
to find that 1 mol % of 1 catalyzed the reaction with good
conversion and enantioselectivity (Table 1, entry 1). Variations
in the catalyst structure revealed that the homologous and more
soluble catalyst H-D-Pro-Pro-Glu-NH2 2 bearing an additional
methylene group is an even better catalyst (Table 1, entry 2).
Notably, the product of a homoaldol reaction of the aldehyde
that is often observed with other amine-based organocatalysts
was not detected at all with catalytically active peptide 2. This
allowed for reducing the amount of aldehyde to as little as 1.5
equiv with respect to nitroethylene. Among the common reaction
parameters, the concentration was particularly important. At a
nitroethylene concentration of 0.1 M in chloroform, the product
was obtained with significantly higher enantioselectivity com-
pared to that of reactions performed at higher or lower
concentration (Table 1, entry 5). Thus, the best results (95%
With these reaction parameters defined, we reacted a range
of different aldehydes with nitroethylene in the presence of 1
mol % of peptide 2 (Table 2). Since the resulting R-substituted
γ-nitroaldehydes are prone to racemization upon purification
by column chromatography, they were typically reduced to the
corresponding alcohols before isolation. The conjugate addition
reaction products were obtained in high yields and excellent
enantioselectivities for a range of different aliphatic and
functionalized aldehydes. Particularly notable is that, with
slightly higher amounts of catalyst (3 mol %) and longer reaction
times, not only isovaleraldehyde but even neopentylaldehyde
with a tert-butyl group at the R-carbon is tolerated as a substrate
(Table 2, entries 5 and 6). In addition, aldehydes bearing
functional groups such as alkenes and esters also reacted readily
with nitroethylene in the presence of only 1 mol % of peptide
2 (Table 2, entries 8–10).
We assume that the reactions proceed via enamine catalysis2e
since methylation or acetylation of the N-terminal proline residue
of 2 led to inactive catalysts. Interestingly, peptide H-D-Pro-
Pro-Gln-NH2 (4) with a carboxamide in place of the carboxylic
acid is a poorer catalyst with respect to its reactivity but
exhibited comparable selectivity. This result suggests that in
9
5610 J. AM. CHEM. SOC. 2008, 130, 5610–5611
10.1021/ja801027s CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. 1,4-Addition Reactions between Aldehydes and
Nitroethylene Catalyzed by Peptide 2a
the European Union. H.W. is grateful to Bachem for an endowed
professorship. We thank Prof. S. H. Gellman for sharing
unpublished results. This paper is dedicated to Andreas Pfaltz,
an excellent scientist and wonderful colleague.
Supporting Information Available: Experimental details on the
syntheses and analyses of the presented compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
entry
R
time (h)
yieldb (%)
eec (%)
1
2
3
4
Me
Et
20
15
15
20
45
120
15
25
70
25
84
82
90
84
85
67
82
86
78
80
95
98
99
99
97d
98
98
98
95
96
n-Pr
n-Bu
i-Pr
t-Bu
Bn
References
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6e
7
8f
9f
10f
(CH2)5CHdCHCH2CH3
CH2CO2CH3
CH2CH2CH2CO2CH3
a Reactions were performed using the TFA salt of
2
and the
equivalent amount of N-methylmorpholine (NMM). b Isolated yield.
c Determined by chiral phase HPLC or GC analysis. d The ee was
determined by an 1H NMR spectroscopic analysis of the aldehyde (ref
9; see Supporting Information). e 3 mol % of 2 and NMM was used.
f Yield and ee were determined for the aldehyde (ref 11; see Supporting
Information).
Scheme 1. Synthesis of γ2-Amino Acids from γ-Nitroalcohols
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17, 989. (d) Xu, Y.; Zou, W.; Sundén, H.; Ibrahem, I.; Córdova, A. AdV.
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contrast to direct aldol reactions, where an acidic functional
group within the catalyst is a prerequisite for efficient catalysis,12
conjugate addition reactions of aldehydes to nitroethylene
require simply a coordinating functional group within the
catalyst structure.10
Conversion of the conjugate addition products to γ2-amino
acids proved straightforward. As an illustration, nitroalcohol 3g
was oxidized to the carboxylic acid using Jones reagent followed
by reduction of the nitro group with Raney-Ni and Fmoc
protection of the resulting amino acid. The Fmoc-protected γ2-
amino acid 5g was obtained in an overall yield of 81% with
retention of optical purity as determined by reaction of 5g with
a chiral amine (Scheme 1a). In addition, 3g was readily
converted into the γ-lactone 6g which was used to assign the
absolute configuration (Scheme 1b).3d,13 Such monosubstituted
γ-lactones are also useful precursors to a multitude of biologi-
cally active compounds.14
(10) Experiments with the inner salt of 2 in the absence of NMM proceeded
with the same enantioselectivity but significantly slower. This could suggest
that TFA influences the catalytic activity; however, the inner salt proved
also not entirely soluble.
(11) The enantiomeric purity was determined by 1H NMR spectroscopy after
reacting the γ-amino aldehydes with a chiral amine to form diastereomeric
imines (ref 9). Control experiments with substrates that allowed for the
analysis of the ee both on the aldehyde and alcohol stage verified that this
method is exact within an error of (2% ee.
In conclusion, peptide 2 is an excellent asymmetric catalyst
for conjugate addition reactions of aldehydes to nitroethylene,
affording monosubstituted γ-nitroaldehydes in high yields and
enantioselectivities requiring only a small excess of the aldehyde
and as little as 1 mol % of the catalyst. The products can be
readily converted into monosubstituted γ2-amino acids, which
should thus facilitate research on the development of therapeutics
and foldamers consisting of γ2-amino acids.15
(12) (a) Revell, J. D.; Wennemers, H. Tetrahedron 2007, 63, 8420. (b) Krattiger,
P.; Kovàsy, R.; Revell, J. D.; Ivan, S.; Wennemers, H. Org. Lett. 2005, 7,
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125, 11253. (b) Caro, Y.; Masaguer, C. F.; Ravina, E. Tetrahedron:
Asymmetry 2001, 12, 1723.
(14) For a review see Sefkow, M. Top. Curr. Chem. 2004, 243, 185.
(15) For a closely related study, see: Chi, Y.; Guo, L.; Kopf, N. A.; Gellman,
S. H J. Am. Chem. Soc. 2008, 130, xxxx.
Acknowledgment. This work was supported by Bachem, the
Swiss National Science Foundation, and the RTN REVCAT by
JA801027S
9
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