Adapting to substrate challenges: Peptides as catalysts for conjugate addition reactions of aldehydes to α,β-disubstituted nitroolefins

Article abstract of DOI:10.1002/chem.201102484

Conjugate addition reactions of aldehydes to α,β-disubstituted nitroolefins are important because they provide synthetically useful γ-nitroaldehydes bearing three consecutive stereogenic centers. Such reactions are challenging due to the drastically lower reactivity of α,β-disubstituted nitroolefins compared to, for example, β-monosubstituted nitroolefins. The testing of a small collection of peptides of the type Pro-Pro-Xaa (Xaa=acidic amino acid) led to the identification of H-Pro-Pro-D-Gln-OH and H-Pro-Pro-Asn-OH as excellent stereoselective catalysts for this transformation. In the presence of 5a mol% of these peptides different combinations of aldehydes and α,β- disubstituted nitroolefins react readily with each other providing γ-nitroaldehydes in good yields and diastereoselectivities as well as excellent enantioselectivities. Chiral pyrrolidines as well as fully substituted γ-butyrolactams and γ-amino acids are easily accessible from the γ-nitroaldehydes. Mechanistic studies demonstrate that the configuration at all three stereogenic centers is induced by the peptidic catalysts. Only a minimal amount of products from homo-aldol reactions is observed demonstrating the high chemoselectivity of the peptidic catalysts. α,β- Disubstituted nitroolefins are challenging electrophiles due to their low reactivity. The modular nature of peptides of the type Pro-Pro-Xaa (Xaa=acidic amino acid; see scheme) allowed for the identification of H-Pro-Pro-D-Gln-OH and H-Pro-Pro-Asn-OH as very good catalysts for the conjugate addition reaction of aldehydes to α,β-disubstituted nitroolefins. Mechanistic studies demonstrate that the peptides induce the configuration at each of the stereogenic centers. Copyright

Full text of DOI:10.1002/chem.201102484

FULL PAPER
DOI: 10.1002/chem.201102484
Adapting to Substrate Challenges: Peptides as Catalysts for Conjugate
Addition Reactions of Aldehydes to a,b-Disubstituted Nitroolefins
Jçrg Duschmalꢀ[a, b] and Helma Wennemers*[a, b]
Abstract: Conjugate addition reactions
of aldehydes to a,b-disubstituted nitro-
olefins are important because they pro-
vide synthetically useful g-nitroalde-
hydes bearing three consecutive stereo-
genic centers. Such reactions are chal-
lenging due to the drastically lower re-
d-Gln-OH and H-Pro-Pro-Asn-OH as
excellent stereoselective catalysts for
this transformation. In the presence of
5 mol% of these peptides different
combinations of aldehydes and a,b-di-
substituted nitroolefins react readily
with each other providing g-nitroalde-
hydes in good yields and diastereose-
lectivities as well as excellent enantio-
selectivities. Chiral pyrrolidines as well
as fully substituted g-butyrolactams
and g-amino acids are easily accessible
from the g-nitroaldehydes. Mechanistic
studies demonstrate that the configura-
tion at all three stereogenic centers is
induced by the peptidic catalysts. Only
a minimal amount of products from
homo-aldol reactions is observed dem-
onstrating the high chemoselectivity of
the peptidic catalysts.
activity of a,b-diACHTUNGTRENNUNGsubstituted nitroolefins
compared to, for example, b-monosub-
stituted nitroolefins. The testing of a
small collection of peptides of the type
Pro-Pro-Xaa (Xaa=acidic amino acid)
led to the identification of H-Pro-Pro-
Keywords: addition reactions
·
asymmetric catalysis · nitroolefins ·
peptides · proline
Introduction
acids or g-butyrolactams (Scheme 1). Progress has likely
been hampered by the lower reactivity of a,b-disubstituted
nitroolefins compared to their b-monosubstituted counter-
Conjugate addition reactions of carbon-based nucleophiles
À
to electron-deficient olefins are among the most useful C C
bond forming processes.[1] In particular, the conjugate addi-
tion of aldehydes to b-substituted nitroolefins is one of the
most widely researched reactions, because the resulting g-ni-
troaldehydes are versatile intermediates that can be readily
transformed into a variety of useful building blocks includ-
ing chiral g-amino acids, g-butyrolactams, and pyrrolidines.[2]
Consequently, manifold chiral-amine-based catalysts have
been explored that promote the conjugate addition reaction
of aldehydes to b-substituted nitroolefins.[3–7] However, ex-
amples of addition reactions of carbonyl compounds to ni-
troolefins, which bear not only a substituent in the b- but
also in the a-position, are rare.[8–12] The development of con-
jugate addition reactions of aldehydes to such a,b-disubsti-
tuted nitroolefins is highly desirable, as the resulting g-nitro-
aldehydes bear three consecutive stereogenic centers and
are therefore valuable intermediates for the synthesis of, for
example, chiral pyrrolidines and fully substituted g-amino
Scheme 1. Conjugate addition reactions of aldehydes to a,b-disubstituted
nitroolefins.
parts as well as difficulties in controlling the absolute config-
uration at the carbon atom bearing the nitro group. In fact,
the only a,b-disubstituted nitroolefins that have been ex-
plored in organocatalytic conjugate addition reactions with
aldehydes are either cyclic[8,9] or profit from activation of
the nitro group by an intramolecular hydrogen-bond
donor.[10] A single example of the addition of an aldehyde to
an acyclic non-activated disubstituted nitroolefin in the
course of a total synthesis provided the product in low dia-
stereoselectivity due to poor control of the stereogenic
center at the carbon atom bearing the nitro group.[11]
Our group has recently introduced peptides of the general
type Pro-Pro-Xaa, where the turn inducing Pro-Pro-motive
is combined with a C-terminal acidic amino acid (Xaa), as
effective catalysts for enamine catalysis.[5–7,13] For example,
the peptide H-d-Pro-Pro-Glu-NH2 (1a) is an excellent cata-
lyst for conjugate addition reactions of aldehydes to b-mon-
osubstituted nitroolefins.[5–7] In the presence of as little as
ꢀ1 mol% of 1a a broad variety of aldehydes react readily
with both aliphatic and aromatic nitroolefins to provide the
corresponding g-nitroaldehydes in very good yields and ste-
[a] J. Duschmalꢀ, Prof. Dr. H. Wennemers
Department of Chemistry, University of Basel
St. Johanns-Ring 19, CH-4056 Basel (Switzerland)
[b] J. Duschmalꢀ, Prof. Dr. H. Wennemers
Laboratorium fꢁr Organische Chemie, ETH Zꢁrich
Wolfgang-Pauli-Strasse 10, CH-8093 Zꢁrich (Switzerland)
E-mail: Helma.Wennemers@org.chem.ethz.ch
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102484.
Chem. Eur. J. 2012, 18, 1111 – 1120
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1111

Table 1. 1,4-Addition reactions of butanal to b-nitrostyrene (2a) and the
a,b-disubstituted nitroolefin 2b catalyzed by the tripeptide H-d-Pro-Pro-
Glu-NH2 1a.[a]
reoselectivities. In contrast to many other chiral secondary-
amine-based catalysts, peptide 1a strongly favors the conju-
gate addition reaction over competing homo-aldol reactions
of the aldehyde.[6] This high chemoselectivity of the peptidic
catalyst 1a is remarkable, in particular because the closely
related peptide H-Pro-Pro-Asp-NH2 is a very good catalyst
for aldol reactions.[13] It demonstrates that slight variations
in the structure of peptides of the type Pro-Pro-Xaa allow
for a fine tuning of their chemoselectivity. A high chemose-
lectivity for conjugate addition reactions over homo-aldol
reactions becomes even more important when less reactive
substrates, such as a,b-disubstituted nitroolefins, are em-
ployed. The unique catalytic performance combined with
the modular nature of the Pro-Pro-Xaa motif, which allows
for accessing a variety of structurally different catalysts
easily by standard solid-phase peptide synthesis, suggested
to us that this class of peptidic catalysts might contain mem-
bers capable of catalyzing conjugate addition reactions be-
tween aldehydes and a,b-disubstituted nitroolefins. Here we
present the peptides H-Pro-Pro-d-Gln-OH and H-Pro-Pro-
Asn-OH as effective stereoselective catalysts for addition
reactions between aldehydes and a,b-disubstituted nitroole-
fins. We also demonstrate that the resulting g-nitroaldehydes
can be further converted into chiral pyrrolidines as well as
fully substituted g-butyrolactams and g-amino acids.
R
1a
[mol%]
Solvent
t
Conv d.r.[b]
[%][b]
ee
G
[h]
[%][c]
1[d]
2
H
1
5
5
CHCl3/iPrOH
9:1
CHCl3/iPrOH 150
9:1
12 100
42:1
97
Me
Me
30
40
86:8:3:3
99
3
CHCl3/iPrOH 150
67:15:10:8 98
1:9
[a] Reactions were typically carried out with the trifluoroacetic acid
(TFA) salt of the peptide and the equivalent amount of N-methylmor-
pholine (NMM). The same results were obtained with the “desalted”
1
peptide without NMM. [b] Diastereomeric ratio; determined by H NMR
spectroscopy of the crude reaction mixture. [c] Enantiomeric excess; de-
termined by chiral-phase HPLC analysis. [d] Data from reference [6].
Results and Discussion
Reactivity of a,b-disubstituted nitroolefins: We started our
investigations by testing peptide 1a as a catalyst for the con-
jugate addition reaction of butanal to b-methyl-b-nitrostyr-
ene (2b). This nitroolefin was chosen as a test substrate, be-
cause it is an acyclic a,b-disubstituted nitroolefin that is nei-
ther activated by an intramolecular hydrogen bond to the
nitro group nor by an electron-withdrawing group on the
phenyl ring. Nitroolefin 2b should therefore represent a
non-activated a,b-disubstituted nitroolefin and proved
indeed to be significantly less reactive than b-monosubstitut-
ed nitroolefins such as b-nitrostyrene (2a) that react readily
in the presence of 1 mol% of peptide 1a (Table 1, entry 1).
Nevertheless, in the presence of 5 mol% of the peptidic cat-
alyst 1a, 30% conversion to the desired addition product
was observed also with nitroolefin 2b within days by using
conditions that had previously been optimized for the addi-
tion of aldehydes to b-monosubstituted nitroolefins (Table 1,
entry 2).[6] Remarkably, the g-nitroaldehyde was obtained in
a good diastereomeric ratio of 86:8:3:3 and an excellent
enantioselectivity of 99% ee of the major diastereoisomer.
The reactivity of catalyst 1a proved to be higher when ali-
phatic alcohols were used as the main solvent.[6,14] although
at the expense of the stereoselectivity (Table 1, entry 3). To
rationalize the reduced reactivity of b-methyl-b-nitrostyrene
compared to b-nitrostyrene we had a closer look at the
structure of 2b and other a,b-disubstituted nitroolefins.
Comparison of the X-ray crystal structures of 2a and 2b re-
vealed a distinct difference (Scheme 2). Whereas 2a is a
Scheme 2. X-ray crystal structures of trans-b-nitrostyrene (2a, top)[15] and
trans-b-methyl-b-nitrostyrene (2b, bottom).
planar molecule, the phenyl ring in 2b is twisted with re-
spect to the plane of the nitroalkene. Such a twist is not
only responsible for an increased steric demand of nitroole-
fin 2b, but also hampers conjugation of the double bond
with the aromatic ring and thereby renders the a,b-disubsti-
tuted nitroolefin less reactive compared to b-nitrostyrene. A
similar deviation from a planar geometry is observed for
most a,b-disubstituted trans-nitroolefins in the Cambridge
Structural Database (see the Supporting Information for de-
tails). This distinct structural difference between b-mono-
and a,b-disubstituted nitroolefins is also supported by ab
initio calculations (MP2/cc-pVTZ) of nitroolefin 2b (see the
Supporting Information). These results show, that the drasti-
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Chem. Eur. J. 2012, 18, 1111 – 1120

Peptides as Catalysts for Conjugate Addition Reactions
FULL PAPER
cally reduced reactivity of a,b-disubstituted nitroolefins is
due to both, an increased steric demand of the additional a-
substituent and a stereoelectronic effect.
and amide moieties. This collection of peptides was pre-
pared by using the 9-fluorenylmethoxycarbonyl/tert-butyl
(Fmoc/tBu) protocol for standard solid-phase peptide syn-
thesis. Within a few days ꢁ50 mg of each peptide were pre-
pared on a parallel peptide synthesizer demonstrating the
ease of accessing a variety of peptides of the type Pro-Pro-
Xaa. All of the fifteen different tripeptides proved to cata-
lyze the conjugate addition reaction and provided the prod-
ucts in moderate to very good stereoselectivities (Table 2).
Their catalytic reactivities and stereoselectivities differed,
however, quite significantly depending on the stereochemis-
try of all three amino acids as well as the position of the car-
boxylic acid. The best catalysts with respect to both catalytic
activity and stereoselectivity proved to be the peptides H-
Pro-Pro-d-Gln-OH (1i) and H-Pro-Pro-Asn-OH (1n)
(Table 2, entries 9 and 14). With both peptides the conjugate
addition product was obtained in good diastereoselectivities
(84:10:5:1 for 1i and 82:12:4:2 for 1n), excellent enantiose-
lectivities of the major stereoisomer (99% ee), and full con-
version is observed within 3 d.[16] Both peptides differ from
the parent catalyst 1a in the stereochemistry of the Pro–Pro
motive (l–l versus d–l) and the position of the carboxylic
acid, which is within 1i and 1n at the C terminus of the pep-
tides and not in the side chain. Rationalizing the reason for
the optimal performance of peptides 1i and 1n is not trivial
because tripeptides have typically not only one preferred
conformation. Whereas the Pro–Pro motive provides confor-
mational rigidity,[17] the C-terminal part can be assumed to
be rather flexible. It is likely that this combination of a cer-
tain degree of conformational flexibility and rigidity is key
to the catalytic efficiency of peptides of the type Pro-Pro-
Xaa in general. Studies with analogues of 1i and 1n in
which the secondary amine and/or the carboxylic acid are
replaced by other functional groups demonstrate that both
functional groups are crucial for effective catalysis. In
accord with previous studies, diastereomeric peptides bear-
ing d-Pro versus l-Pro residues at the N terminus have op-
posite enantioselectivities (for example, peptides 1a and 1b,
Table 2, entries 1 and 2). This is due to the opposite orienta-
tions of N-terminal d-Pro versus l-Pro residues relative to
the rest of the peptide (for details see reference [5a]). An
evaluation of the peptides 1i and 1n as catalysts for the con-
jugate addition between butanal and b-monosubstituted ni-
trostyrene demonstrated that both perform significantly
poorer compared to peptide 1a.[18] This shows that the dif-
ferent properties of b-monosubstituted versus a,b-disubsti-
tuted nitroolefins are optimally addressed by similar yet dif-
ferent peptidic catalysts. These results demonstrate that fif-
teen different peptides of the type Pro-Pro-Xaa were suffi-
cient to identify two very good catalysts for conjugate addi-
tion reactions with a,b-disubstituted nitroolefins. It
highlights the ease with which the catalytic activity, stereose-
lectivity, and chemoselectivity of peptides of the Pro-Pro-
Xaa class can be fine-tuned by subtle structural modifica-
tions to accommodate the requirements of different sub-
strate combinations.
Catalyst screening: The initial results demonstrated that de-
spite the low reactivity of a,b-disubstituted nitroolefins the
peptidic catalyst 1a allows for conversion to the desired con-
jugate addition product with a very good control over the
enantio- and diastereoselectivity of all three stereogenic
centers including that at the carbon atom bearing the nitro
group. In addition, the structural analysis of the nitroolefin
2b showed that the geometry of a,b-disubstituted nitroole-
fins differs significantly from that of monosubstituted ana-
logues. Based on these findings we hypothesized that a
structurally related peptide of the type Pro-Pro-Xaa might
be better suited to catalyze reactions of a,b-disubstituted ni-
troolefins compared to peptide 1a that was optimized to ac-
commodate b-monosubstituted nitroolefins. Thus, we syn-
thesized and tested a small collection of fifteen different tri-
peptides of the type Pro-Pro-Xaa (1b–p, Table 2) as cata-
lysts for the conjugate addition reaction of butanal with ni-
troolefin 2b. Variations included 1) the stereochemistry of
all three residues and thereby the geometry of the turn
structure, 2) the position of the carboxylic acid either at the
C terminus or in the side chain of the C-terminal amino
acid, and 3) the length of the spacer to the carboxylic acid
Table 2. 1,4-Addition reactions of butanal to b-methyl-b-nitrostyrene
(2b) catalyzed by different tripeptides of the type Pro-Pro-Xaa.[a]
Catalyst
t
Conv d.r.[b]
ee
[h] [%][b]
[%][c]
1
2
3
4
5
6
7
8
H-d-Pro-Pro-Glu-NH2 (1a)
H-Pro-Pro-Glu-NH2 (1b)
H-Pro-d-Pro-Glu-NH2 (1c)
H-Pro-Pro-d-Glu-NH2 (1d)
H-Pro-Pro-Asp-NH2 (1e)
H-Pro-Pro-d-Asp-NH2 (1 f)
H-Pro-Pro-b-homo-Asp-OH (1g)
H-d-Pro-d-Pro-b-homo-Asp-OH
(1h)
150 40
150 100
150 40
150 85
72 100
150 100
84 100
150 90
67:15:10:8 98[d]
67:16:10:7 96
48:23:19:10 91
55:21:15:9 96
71:18:6:5
97
65:17:10:8 96
75:15:6:4
70:13:9:8
97
98[d]
9
H-Pro-Pro-d-Gln-OH (1i)
54 100
150 100
150 30
150 40
54 100
54 100
150 60
150 50
84:10:5:1
66:21:8:5
99
97
10 H-Pro-Pro-Gln-OH (1j)
11 H-d-Pro-Pro-Gln-OH (1k)
12 H-Pro-d-Pro-Gln-OH (1l)
13 H-Pro-Pro-d-Asn-OH (1m)
14 H-Pro-Pro-Asn-OH (1n)
15 H-d-Pro-Pro-Asn-OH (1o)
16 H-Pro-Pro-cysteic acid-NH2 (1p)
42:27:19:12 84[d]
48:20:17:15 86
75:16:6:3
82:12:4:2
97
99
42:27:18:13 90[d]
53:17:17:13 89
[a] Reactions were typically carried out with the TFA salt of the peptide
and the equivalent amount of NMM. The same results were obtained
with the “desalted” peptide without NMM. [b] Determined by 1H NMR
spectroscopy of the crude reaction mixture. [c] Determined by chiral-
phase HPLC analysis. [d] The opposite enantiomer of the major diaste-
reoisomer was obtained.
Chem. Eur. J. 2012, 18, 1111 – 1120
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1113

H. Wennemers and J. Duschmalꢀ
Table 3. Ratio of the diastereoisomers of g-nitroaldehyde 3 formed in
the presence of different secondary amines.
Do the peptides control the configuration at each stereogen-
ic center? Determination of the relative configuration of
compounds 3: Next, we sought to examine whether and the
extent to which the catalysts control the configuration at all
three stereogenic centers, formed in the conjugate addition
reaction. Mechanistically, the stereochemistry at C(2) and
À
C(3) is installed during the C C bond formation step I,
when the enamine, derived from the aldehyde and the cata-
lyst, reacts with the nitroolefin (Scheme 3). The resulting ni-
Entry
Catalyst
A[a]
B
C
D
1
2
3
4
pyrrolidine
proline
H-Pro-Pro-d-Gln-OH ACTHNUTRGNE(UNG 1i)
H-Pro-Pro-Asn-OH
22
32
84
82
18
16
10
12
40
36
5
20
16
1
A
4
2
[a] Diastereoisomer A was obtained with 31% ee (proline) and 99% ee
(peptidic catalysts 1i and 1n).
isomer formed in the presence of the tripeptides is the
major isomer formed in the presence of both proline and
pyrrolidine. These results demonstrated immediately that
the tripeptides control and overwrite the intrinsically pre-
ferred relative configuration of the g-nitroaldehydes.[21]
These reactions also allowed for isolating the four diastereo-
isomers in sufficient quantities to analyze their relative con-
figurations by NMR spectroscopy. This was achieved after
converting the diastereomeric g-nitroaldehydes to the N-to-
sylated pyrrolidines 4 (Scheme 4). They were obtained in
Scheme 3. Putative catalytic cycle of the peptide-catalyzed conjugate ad-
dition reaction of aldehydes to a,b-disubstituted nitroolefins. The two ste-
reogenic centers at C(2) and C(3) are formed in the conjugate addition
step I, whereas the center at C(4) is formed in a subsequent protonation
of the intermediate nitronate (step II).
tronate, which is thought to be stabilized by coordination to
the carboxylic acid moiety of the catalyst,[6,19] is then subse-
quently protonated (step II), which sets the absolute config-
uration of the third stereogenic center (C(4)). We expected
À
that the geometry of the C C bond formation step would be
similar to that of our previously examined addition reactions
between aldehydes and b-monosubstituted nitroolefins and
therefore assumed a relative syn configuration at C(2) and
C(3). The diastereoselectivity at C(4) is less obvious because
it could either be controlled by the catalyst or the already
formed stereogenic centers at C(2) and C(3). To analyze the
extent to which the peptidic catalysts control the stereo-
chemistry at each of the stereogenic centers, butanal and ni-
troolefin 2b were also allowed to react in the presence of
achiral pyrrolidine. In addition, proline was used as a cata-
lyst to determine the effect of the additional two residues
within the tripeptide. These experiments allowed for the for-
mation of all four diastereoisomers, albeit a major side prod-
uct or even the main product was in both cases the product
of homo-aldol reactions.[20] In the presence of pyrrolidine
Scheme 4. Conversion of the isolated individual diastereoisomers of reac-
tion product 3a to the corresponding N-tosylated pyrrolidines 4 (top).
Observed strong long range NOEs within the three analyzed diastereo-
isomers A–C (bottom).
two steps by reductive amination by using palladium hy-
droxide on activated charcoal in a hydrogen atmosphere
(4.5 bar) followed by tosylation of the resulting pyrrolidines.
Analysis of the coupling constants and the NOEs observed
in one- and two-dimensional NMR spectra allowed for the
unambiguous determination of the relative configuration of
the diastereoisomers of three of the four pyrrolidines 4 and
thereby also those of the g-nitroaldehydes (see the Support-
ing Information for details). The analysis revealed that the
the four diastereoisomers were formed in
a
ratio of
relative configuration of the major diastereoisomer
A
22:18:40:20, the ratio was 32:16:36:16 when proline was
used. Thus, the distribution of the four diastereoisomers dif-
fers significantly from those observed with the tripeptides
(Table 3). For example, the third most abundant diastereo-
formed in the peptide-catalyzed reaction has the rel-ACHTUNG-
TERNN(UG 2R,3S,4R)-configuration (A, Table 3; for the determination
of the absolute configuration see below).[22] Thus, as expect-
ed from the related reactions with b-monosubstituted nitro-
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Peptides as Catalysts for Conjugate Addition Reactions
FULL PAPER
olefins, the major diastereoisomer has a syn relative configu-
ration with respect to the stereogenic centers C(2) and C(3).
The second most abundant diastereoisomer has the rel-AHCTUNG-
with the relative syn,anti configuration determined above
for the major diastereoisomer. The stereochemical prefer-
ence of the reaction is therefore analogous to that observed
in the peptide-catalyzed conjugate addition reactions be-
tween aldehydes and b-monosubstituted nitroolefins demon-
strating the similarity of the transition states.
TRENNUNG
AHCTUNGTRENNUNG
mers of A and B, respectively, with opposite absolute config-
urations at C(4), the carbon atom bearing the nitro group
that is installed in the protonation of the nitronate. These
epimers form in significantly different ratios (A/C and B/D)
in the peptide-catalyzed reactions, whereas they are either
identical or have a reversed preference in the reactions per-
formed in the presence of pyrrolidine and proline (Table 3).
This demonstrates that the protonation step is controlled by
the peptidic catalysts and not by the stereochemistry at C(2)
and C(3). The higher abundance of B compared to C in the
peptide-catalyzed reactions indicates that the protonation of
Substrate scope: To probe the substrate scope of the pep-
tide-catalyzed conjugate addition reactions different combi-
nations of aldehydes and a,b-disubstituted nitroolefins were
allowed to react in the presence of 5 mol% of the two opti-
mal catalysts H-Pro-Pro-d-Gln-OH (1i) and H-Pro-Pro-
Asn-OH (1n) (Table 4). To facilitate the isolation of diaste-
reomerically pure samples and to prevent epimerization at
Table 4. Scope of 1,4-addition reactions of aldehydes to a,b-disubstituted
nitroolefins.[a]
À
the nitronate is even more stereoselective than the C C
bond formation.
Determination of the absolute configuration of the main
conjugate addition product: To determine the absolute con-
figuration of the major diastereoisomer formed in the pep-
tide-catalyzed reaction, g-nitrocarboxylic acid 5, derived
from oxidation of g-nitroaldehyde 3b (see below), was cou-
pled to the methyl ester of l-phenylalanine (Scheme 5). The
Product
Catalyst Yield d.r.[c]
[%][b]
ee
[%][d]
1i
81
88
84:10:5:1
82:12:4:2
99
99
1n
1[e]
1i
1n
65
74
87:8:4:1
87:7:3:3
99
99
2
1i
1n
73
72
83:10:6:1
83:9:7:1
99
99
3[f]
4[f]
5
1i
1n
87
89
77:15:6:2
85:11:3:1
97
99
1i
1n
98
90
74:18:6:2
72:19:6:3
98
99
1i
1n
77
75
75:13:9:3
71:17:8:4
99
99
6
Scheme 5. Determination of the absolute configuration of the major
isomer of the g-nitroaldehyde by synthesis (top) and crystal structure
analysis of dipeptide 6 (bottom).
1i
1n
81
73
86:7:6:1
86:7:5:2
99
98
7
resulting protected dipeptide 6 is a crystalline solid and crys-
tals suitable for X-ray crystal structural analysis were ob-
tained. The main stereoisomer of the g-nitroaldehyde 3b
produced in the reaction between 3-phenylpropanal and b-
methyl-b-nitrostyrene was thereby unambiguously assigned
to be of the (2R,3S,4R) configuration. This is in agreement
1i
1n
59
61
65:20:10:5
54:29:10:7
94
92
8
Chem. Eur. J. 2012, 18, 1111 – 1120
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1115

H. Wennemers and J. Duschmalꢀ
Synthesis of g-butyrolactams and g-amino acids: As demon-
strated above, the obtained fully substituted g-nitroalde-
hydes can be easily converted to chiral pyrrolidines with
three consecutive stereogenic centers. Equally as versatile
for medicinal chemistry as well as research on foldamers are
chiral fully substituted g-butyrolactams and g-amino
acids.[24–26] The syntheses of chiral g-amino acids rely mostly
on either chiral resolution or the use of chiral auxiliaries.[27]
Direct catalytic enantioselective methods furnishing these
building blocks are therefore highly desirable. g-Nitroalde-
hyde 3b was chosen as a model compound for the synthesis
of g-butyrolactams and g-amino acids because it is a crystal-
line solid that was obtained in diastereomerically and enan-
tiomerically pure form by a simple precipitation from pen-
tane. The synthesis of the g-butyrolactam 7 and the g-amino
acid 8 proved to be straightforward (Scheme 6). Jones oxida-
Table 4. (Continued)
Product
Catalyst Yield d.r.[c]
[%][b]
ee
[%][d]
1i
1n
71
80
71:26
66:30
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
9[f]
1i
1n
66
66
61:29:7:3
58:31:7:4
98
98
10
1i
1n
74
72
79:9:8:4
72:14:8:6
99
99
11
[a] Reactions were typically carried out with the TFA salt of the peptide
and the equivalent amount of NMM. The same results were obtained
with the “desalted” peptide without NMM. [b] Yields correspond to g-ni-
troaldehydes isolated as a mixture of diastereoisomers. [c] Determined
by 1H NMR spectroscopy of the crude reaction mixture. [d] Determined
by chiral-phase HPLC analysis of the isolated major diastereoisomers of
the corresponding d-nitroalcohols obtained after NaBH4 reduction.
[e] The enantiomeric excess was determined at the level of the g-nitroal-
dehyde. [f] Reaction times of 4–5 d were necessary.
C(2), the resulting g-nitroaldehydes were isolated from the
catalysis reaction and then reduced to the corresponding d-
nitroalcohols by using NaBH4. In all cases diastereomerical-
ly pure samples of the major diastereoisomers were ob-
tained by column chromatography or semi preparative
HPLC. In general, both catalysts performed similarly well in
all of the reactions examined. Variations in the aldehyde
(Table 4, entries 1–5) as well as in the nitroolefin (Table 4,
entries 6–11) are well tolerated. The products were obtained
with at least one of the two catalysts in yields of generally
>70%. The excess of the main diastereoisomer was typical-
ly >70% and the major stereoisomer was often obtained in
perfect enantioselectivity. Aldehydes with sterically more
demanding moieties in the b-position required longer reac-
tion times but provided the addition products also in good
yields and very good stereoselectivities (Table 4, entries 2–
4). Also an aldehyde bearing an ester moiety reacted readily
with the nitroolefins (Table 4, entries 5 and 8). Variations at
both the a- and the b-position of aromatic nitroolefins are
tolerated (Table 4, entries 6–10) and provided the products
in very good stereoselectivities. Only a,b-disubstituted nitro-
olefins bearing aromatic substituents in both positions
proved to be too unreactive to allow for product forma-
tion.[23] In addition, also the cyclic, aliphatic nitrocyclohex-
ene was successfully converted to the conjugate addition
product (Table 4, entry 11) in good yields and stereoselectiv-
ities. These results demonstrate that the peptides 1i and 1n
are very good catalysts for conjugate addition reactions of a
broad range of different aldehydes and a,b-disubstituted ni-
troolefins.
Scheme 6. Synthesis of the fully substituted lactam 7 and the Fmoc-pro-
tected g-amino acid 8 from g-nitroaldehyde 3b (Ac=acyl).
tion of g-nitroaldehyde 3b provided the g-nitrocarboxylic
acid 5 in a yield of 98%. Carboxylic acid 5 served then as
the common precursor en route to both, the fully substituted
g-butyrolactam 7 as well as the trisubstituted g-amino acid
8. Lactam 7 was easily prepared through methyl ester 9 fol-
lowed by reduction of the nitro group by using zinc in an
acidic environment. Under these conditions the intermedi-
ate g-amino ester cyclizes spontaneously to form lactam 7.
Use of the bulkier tert-butyl ester 10 instead of the methyl
ester prevents, upon reduction of the nitro group, spontane-
ous cyclization and the open-chain g-amino ester 11 is isolat-
ed in nearly quantitative yield. The corresponding Fmoc-
protected g-amino acid building block 8 ready for standard
solid-phase peptide synthesis is then obtained straightfor-
1116
www.chemeurj.org
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 1111 – 1120

Peptides as Catalysts for Conjugate Addition Reactions
FULL PAPER
General procedure for the reduction of g-nitroaldehydes 3: The isolated
g-nitroaldehyde (220 mmol, 1 equiv) was dissolved in MeOH (1 mL). The
resulting solution was cooled to 08C and NaBH4 (220 mmol, 1 equiv) was
added in one portion. The reaction mixture was stirred at 08C. After con-
sumption of the g-nitroaldehyde the reaction was quenched by the addi-
tion of HOAc (220 mmol, 1 equiv). All volatiles were removed at reduced
pressure and the resulting residue was purified by flash column chroma-
tography on silica gel by eluting with a mixture of pentane and EtOAc.
All d-nitroalcohols were obtained in yields above 85%. Diastereomeri-
cally pure samples were either obtained after flash column chromatogra-
phy on silica gel or by semi preparative HPLC by using a LichroCart
250-4 HPLC-Cartridge (LiChrospher Si 60 5 mm).
wardly through Fmoc protection and deprotection of the
tert-butyl ester.
Conclusion
In conclusion, we have introduced the tripeptides H-Pro-
Pro-d-Gln-OH (1i) and H-Pro-Pro-Asn-OH (1n) as effec-
tive catalysts for conjugate addition reactions of aldehydes
to a,b-disubstituted nitroolefins. In the presence of 5 mol%
of either 1i or 1n synthetically useful g-nitroaldehydes bear-
ing three consecutive stereogenic centers were obtained in
good to excellent yields, diastereoselectivities, and enantio-
meric excesses. Chiral pyrrolidines, g-butyrolactams bearing
three consecutive stereogenic centers, and fully substituted
g-amino acids are easily accessible in good yields from the
g-nitroaldehydes. The research also highlights the versatility
of peptidic catalysts of the general type Pro-Pro-Xaa (Xaa=
acidic amino acid) to accommodate different structural as
well as electronic properties within the substrates. The dis-
tinctly different geometric and electronic properties of a,b-
disubstituted nitroolefins compared to b-monosubstituted ni-
troolefins require a distinctly different catalyst to allow for
efficient reactions of these significantly less reactive electro-
philes. The modular nature of peptides of the type Pro-Pro-
Xaa allowed to solve this challenge by the testing of a small
collection of different yet closely related peptides that are
synthetically easily accessible. The versatility of the peptidic
catalysts is further highlighted by the high chemoselectivity
of 1i and 1n for conjugate addition reactions over homo-
aldol reactions. Thus, peptides of the type Pro-Pro-Xaa are
powerful tools for the fine-tuning of the catalyst structure to
adapt to different substrate combinations and favor desired
reaction pathways.
A
(3a):
Colorless
oil;
1H NMR (400 MHz, CDCl3, 258C): d=9.83 (d, J=1.8 Hz, 1H), 7.35–7.24
(m, 3H), 7.05–6.99 (m, 2H), 5.06–4.97 (m, 1H), 3.39 (dd, J=10.0, 5.3 Hz,
1H), 3.15 (ddt, J=10.0, 3.4, 1.8 Hz, 1H), 1.39 (d, J=6.6 Hz, 3H), 1.58–
1.47 (m, 1H), 1.46–1.25 (m, 1H), 0.75 ppm (t, J=7.5 Hz, 3H); 13C NMR
(100 MHz, CDCl3, 258C): d=203.9, 134.9, 128.9, 128.7, 128.2, 83.5, 52.8,
48.3, 20.5, 17.4, 10.1 ppm; elemental analysis calcd (%) for C13H17NO3: C
66.36, H 7.19, N 5.75; found: C 66.33, H 7.28, N 5.79; the enantiomeric
excess was determined by HPLC by using a Chiracel AS-H column (n-
hexane/iPrOH 99:1, 258C) at 0.5 mLminÀ1, UV detection at l=210 nm:
tRACHTUNGTERN(NUNG minor)=25.0, (major)=28.2 min.
AHCTUNGTERG(NNUN 2R,3S,4R)-2-Benzyl-4-nitro-3-phenylpentanal (3b): Colorless solid;
1H NMR (400 MHz, CDCl3, 258C): d=9.81 (d, J=1.5 Hz, 1H), 7.38–7.29
(m, 3H), 7.24–7.14 (m, 3H), 7.11–7.07 (m, 2H), 6.96 (d, J=6.8 Hz, 2H),
5.03 (dq, J=6.7, 5.4 Hz, 1H), 3.54 (ddt, J=9:9, 4.0, 1.5 Hz, 1H), 3.38 (dd,
J=9.9, 5.4 Hz, 1H), 2.73 (dd, J=14.1, 4.0 Hz, 1H), 2.60 (dd, J=14.1,
9.9 Hz, 1H), 1.38 ppm (d, J=6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3,
258C): d=204.4, 137.1, 134.8, 129.0, 128.9, 128.9, 128.7, 128.4, 126.8, 83.0,
53.4, 49.5, 35.2, 17.3 ppm.
A
Colorless
solid;
1H NMR (400 MHz, CDCl3, 258C): d=7.36–7.14 (m, 8H), 7.08–7.03 (m,
2H), 5.24 (dq, J=7.8, 6.6 Hz, 1H), 3.75 (dd, J=11.0, 3.7 Hz, 1H), 3.49
(dd, J=7.8, 7.1 Hz, 1H), 3.35 (dd, J=11.0, 6.6 Hz, 1H), 2.59 (dd, J=13.6,
3.2 Hz, 1H), 2.43–2.35 (m, 1H), 2.26 (dd, J=13.6, 11.0 Hz, 1H), 1.60 ppm
(d, J=6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3, 258C): d=139.7, 136.2,
129.2, 128.8, 128.6, 128.5, 127.8, 126.3, 84.1, 61.4, 50.4, 42.9, 34.0,
18.2 ppm; elemental analysis calcd (%) for C18H21NO3: C 72.22, H 7.07,
N 4.68; found: C 72.21, H 7.14, N 4.53; the enantiomeric excess was de-
termined by HPLC by using a Chiracel AS-H column (n-hexane/iPrOH
95:5, 258C) at 0.5 mLminÀ1, UV detection at l=210 nm: t
40.2, (major)=77.6 min.
RACHTUNGTRENNUNG(minor)=
AHCTUNGTERG(NNUN 2R,3S,4R)-2-Isopropyl-4-nitro-3-phenylpentanal (3c): Colorless solid;
1H NMR (400 MHz, CDCl3, 258C): d=10.06 (d, J=0.4 Hz, 1H), 7.33–
7.27 (m, 3H), 7.03–6.97 (m, 2H), 4.96–4.89 (m, 1H), 3.38–3.35 (m, 2H),
1.67–1.58 (m, 1H), 1.28 (d, J=6.6 Hz, 3H), 1.11 (d, J=7.2 Hz, 3H),
0.68 ppm (d, J=6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3, 258C): d=
205.4, 134.7, 129.0, 128.7, 128.1, 83.0, 56.6, 47.6, 28.7, 21.8, 17.1, 16.2.
Experimental Section
General aspects and materials: Materials and reagents were of the high-
est commercially available grade and used without further purification.
Reactions were monitored by thin layer chromatography by using Merck
silica gel 60 F254 plates. Compounds were visualized by UV and KMnO4.
Flash chromatography was performed by using Merck silica gel 60, parti-
cle size 40–63 mm. 1H and 13C NMR spectra were recorded on Bruker
DPX 400 (400 MHz) or Bruker BZH NMR (250 MHz) spectrometers.
Chemical shifts are reported in ppm by using TMS or the residual solvent
peak as a reference. HPLC analyses were performed on an analytical
HPLC with a diode array detector from Shimadzu. Bruker Esquire 3000
Plus was used for ESI mass spectrometry. For the synthesis of peptide
catalysts 1 and non-commercially available a,b-disubstituted nitroolefins
2 see the Supporting Information.
AHCTUNGTERG(NNUN 2R,3S,4R)-2-Isopropyl-4-nitro-3-phenylpentan-1-ol: Colorless solid;
1H NMR (400 MHz, CDCl3, 258C): d=7.32–7.26 (m, 3H), 7.10–7.02 (m,
2H), 5.35 (dq, J=6.7, 4.5 Hz, 1H), 4.11 (dd, J=11.4, 3.7 Hz, 1H), 3.82
(dd, J=11.4, 4.9 Hz, 1H), 3.22 (dd, J=10.0, 4.5 Hz, 1H), 2.15–2.08 (m,
1H), 1.50 (dsept, J=6.9, 2.5 Hz, 1H), 1.44 (d, J=6.7 Hz, 3H), 0.92 (d,
J=6.9 Hz, 3H), 0.63 ppm (d, J=6.9 Hz, 3H); 13C NMR (100 MHz,
CDCl3, 258C): d=136.7, 129.0, 128.5, 127.6, 83.4, 60.4, 51.0, 45.8, 27.5,
22.6, 18.0, 16.7 ppm; elemental analysis calcd (%) for C14H21NO3: C
66.91, H 8.42, N 5.75; found: C 66.95, H 8.25, N 5.39; the enantiomeric
excess was determined by HPLC by using a Chiracel AS-H column (n-
hexane/iPrOH 97.5:2.5, 258C) at 0.5 mLminÀ1, UV detection at l=
General procedure for the conjugate addition reactions: To a solution of
the peptide (as the TFA salt, 22.0 mmol, 5 mol%), NMM (22 mmol,
5 mol%), and the aldehyde (880 mmol, 2 equiv) in iPrOH and CHCl3
(9:1, 1 mL) the nitroolefin (440 mmol, 1 equiv) was added. The resulting
solution was agitated at room temperature. After consumption of the ni-
troolefin all volatile components were removed at reduced pressure and
the resulting crude product was purified by flash column chromatography
on silica gel by eluting with a mixture of pentanes and EtOAc to yield g-
nitroaldehydes 3.
210 nm: t
RACHTUNGTNER(NUNG minor)=41.5, (major)=52.7 min.
AHCTUNGERTG(NNUN 2R,3S,4R)-4-Nitro-3-phenyl-2-propylpentanal (3d): Colorless oil;
1H NMR (400 MHz, CDCl3, 258C): d=9.81 (d, J=1.9 Hz, 1H), 7.36–7.24
(m, 3H), 7.11–6.99 (m, 2H), 5.01 (quint, J=6.6 Hz, 1H), 3.39 (dd, J=9.6,
5.8 Hz, 1H), 3.16–3.08 (m, 1H), 1.40 (d, J=6.6 Hz, 3H), 1.38–1.05 (m,
4H), 0.75 ppm (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3, 258C):
d=204.1, 135.0, 128.8, 128.7, 128.2, 83.6, 51.7, 49.0, 29.9, 19.4, 17.4,
14.1 ppm.
Chem. Eur. J. 2012, 18, 1111 – 1120
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1117

H. Wennemers and J. Duschmalꢀ
A
0.5 mLminÀ1, UV detection at l=210 nm: t
RACTHNGUTRENNU(G minor)=32.0, (major)=
38.3 min.
(400 MHz, CDCl3, 258C): d=7.30–7.17 (m, 3H), 7.17–7.12 (m, 2H), 5.19
(dq, J=9.2, 6.6 Hz, 1H), 3.79 (dd, J=10.9, 3.7 Hz, 1H), 3.49–3.43 (m,
1H), 3.31 (dd, J=10.9, 7.7 Hz, 1H), 2.08–1.99 (m, 1H), 1.58 (d, J=
6.6 Hz, 3H), 1.43–1.31 (m, 1H), 1.26–1.13 (m, 2H), 1.10–0.97 (m, 1H),
0.85 ppm (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3, 258C): d=
136.4, 129.1, 128.4, 127.6, 85.0, 62.5, 50.3, 40.6, 29.2, 20.9, 18.3, 14.3 ppm;
elemental analysis calcd (%) for C14H21NO3: C 66.91, H 8.42, N 5.75;
found: C 66.64, H 8.22, N 5.66; the enantiomeric excess was determined
by HPLC by using a Chiracel AS-H column (n-hexane/iPrOH 97.5:2.5,
AHCTUNGTERG(NNUN 5R,6S,7R)-Methyl 5-formyl-7-nitro-6-(4-nitrophenyl)octanoate (3h):
Yellow oil; 1H NMR (400 MHz, CDCl3, 258C): d=9.87 (d, J=1.4 Hz,
1H), 8.22–8.17 (m, 2H), 7.28–7.23 (m, 2H), 5.12–5.04 (m, 1H), 3.69–3.64
(m, 1H), 3.58 (s, 3H), 3.25–3.17 (m, 1H), 2.20–2.13 (m, 2H), 1.59–1.32
(m, 4H), 1.44 ppm (d, J=6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3,
258C): d=202.4, 173.0, 147.9, 142.4, 130.1, 124.1, 83.3, 51.8, 51.4, 48.4,
33.5, 26.9, 21.3, 17.6 ppm.
A
5-(hydroxymethyl)-7-nitro-6-(4-nitrophenyl)octa-
258C) at 0.5 mLminÀ1, UV detection at l=210 nm: t
(minor)=64.8 min.
RACHTUNGTREN(NUNG major)=61.5,
noate: Yellow solid; 1H NMR (400 MHz, CDCl3, 258C): d=8.19–8.12
(m, 2H), 7.38–7.31 (m, 2H), 5.22 (dq, J=8.2, 6.6 Hz, 1H), 3.91 (dd, J=
11.0, 3.9 Hz, 1H), 3.64 (s, 1H), 3.61 (dd, J=8.2, 6.6 Hz, 1H), 3.38 (dd,
J=11.0, 7.2 Hz, 1H), 2.29–2.22 (m, 2H), 2.17–2.07 (m, 1H), 1.75–1.62 (m,
1H), 1.59 (d, J=6.6 Hz, 3H), 1.57–1.44 (m, 1H), 1.28–1.15 (m, 1H),
1.11–0.97 ppm (m, 1H); 13C NMR (100 MHz, CDCl3, 258C): d=173.9,
147.6, 144.3, 130.3, 123.6, 84.2, 61.6, 51.8, 50.0, 40.8, 33.7, 27.0, 22.7,
18.4 ppm; elemental analysis calcd (%) for C13H17NCl2O3: C 55.73, H
6.05, N 7.65; found: C 56.00, H 6.32, N 7.30; the enantiomeric excess was
determined by HPLC by using a Chiracel AS-H column (n-hexane/
iPrOH 90:10, 258C) at 0.5 mLminÀ1, UV detection at l=210 nm: tR-
ACHTUNGTRENNUNG(5R,6S,7R)-Methyl 5-formyl-7-nitro-6-phenyloctanoate (3e): Colorless
1
oil; H NMR (400 MHz, CDCl3, 258C): d=9.84 (d, J=1.8 Hz, 1H), 7.36–
7.23 (m, 3H), 7.06–6.99 (m, 2H), 5.01 (dq, J=6.7, 5.8 Hz, 1H), 3.57 (s,
3H), 3.42 (dd, J=9.6, 5.8 Hz, 1H), 3.19–3.11 (m, 1H), 2.17–2.10 (m, 2H),
1.61–1.37 (m, 4H), 1.42 ppm (d, J=6.7 Hz, 3H); 13C NMR (100 MHz,
CDCl3, 258C): d=203.5, 173.2, 134.8, 128.9, 128.9, 128.4, 83.7, 51.7, 51.7,
48.9, 33.7, 26.9, 21.5, 17.5 ppm.
ACHTUNGTRENNUNG(5R,6S,7R)-Methyl 5-(hydroxymethyl)-7-nitro-6-phenyloctanoate: Color-
less oil; 1H NMR (400 MHz, CDCl3, 258C): d=7.42–7.05 (m, 5H), 5.28–
5.14 (m, 1H), 3.87 (dd, J=11.1, 3.7 Hz, 1H), 3.64 (s, 3H), 3.48 (dd, J=
11.1, 6.7 Hz, 1H), 3.40 (t, J=7.4 Hz, 1H), 2.29–2.21 (m, 2H), 2.16–2.00
(m, 1H), 1.78–1.62 (m, 1H), 1.56 (d, J=6.6 Hz, 3H), 1.56–1.46 (m, 1H),
1.34–1.19 (m, 1H), 1.19–1.02 ppm (m, 1H); 13C NMR (100 MHz, CDCl3,
258C): d=174.1, 136.4, 129.2, 128.5, 127.8, 84.5, 62.1, 51.7, 50.5, 40.8,
33.9, 27.0, 22.8, 18.3 ppm; elemental analysis calcd (%) for C16H23NO5: C
62.12, H 7.49, N 4.53; found: C 61.88, H 7.79, N 4.66; the enantiomeric
excess was determined by HPLC by using a Chiracel AS-H column (n-
hexane/iPrOH 92.5:7.5, 258C) at 0.5 mLminÀ1, UV detection at l=
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
(500 MHz, CDCl3, 258C): d=9.81 (d, J=1.8 Hz, 1H), 7.35–7.27 (m, 3H),
7.07–7.00 (m, 2H), 4.83 (ddd, J=10.1, 5.9, 4.3 Hz, 1H), 3.49 (dd, J=9.7,
5.9 Hz, 1H), 3.08–2.98 (m, 1H), 1.84–1.74 (m, 1H), 1.74–1.64 (m, 1H),
1.58–1.47 (m, 1H), 1.47–1.34 (m, 1H), 0.93 (t, J=7.3 Hz, 3H), 0.76 ppm
(t, J=7.5 Hz, 3H); 13C NMR (126 MHz, CDCl3, 258C): d=203.8, 135.2,
129.0, 128.7, 128.2, 90.8, 53.0, 47.4, 25.1, 20.5, 10.6, 10.3 ppm.
AHCTUNGTRENNUNG
(2R,3S,4R)-2-Ethyl-4-nitro-3-phenylhexan-1-ol: Colorless oil; 1H NMR
(400 MHz, CDCl3, 258C): d=7.34–7.25 (m, 3H), 7.20–7.14 (m, 2H), 5.04
(td, J=8.8, 5.5 Hz, 1H), 3.83 (dd, J=10.9, 3.8 Hz, 1H), 3.55 (dd, J=9.3,
5.8 Hz, 1H), 3.35 (dd, J=10.9, 7.7 Hz, 1H), 2.01–1.88 (m, 3H), 1.37 (dqd,
J=14.9, 7.5, 2.9 Hz, 1H), 1.13–1.05 (m, 1H), 1.02 (t, J=7.3 Hz, 3H),
0.91 ppm (t, J=7.4 Hz, 3H); 13C NMR (126 MHz, CDCl3, 258C): d=
136.5, 129.2, 128.3, 127.6, 91.8, 62.0, 49.2, 42.8, 25.4, 19.9, 12.4, 10.3 ppm;
elemental analysis calcd (%) for C14H21NO2: C 66.91, H 8.42, N 5.57;
found: C 66.74, H 8.19, N 5.42; the enantiomeric excess was determined
by HPLC by using a Chiracel AS-H column (n-hexane/iPrOH 95:5,
210 nm: t
RACHTUNGTRENNUNG(minor)=45.6, (major)=49.1 min.
ACHTUNGTRENNUNG(2R,3S,4R)-2-Ethyl-4-nitro-3-(4-nitrophenyl)pentanal (3 f): Yellow oil;
1H NMR (400 MHz, CDCl3, 258C): d=9.86 (d, J=1.4 Hz, 1H), 8.22–8.18
(m, 2H), 7.29–7.23 (m, 2H), 5.09 (dq, J=6.7, 5.4 Hz, 1H), 3.56 (dd, J=
10.0, 5.4 Hz, 1H), 3.21 (dddd, J=10.0, 8.5, 3.4, 1.4 Hz, 1H), 1.64–1.52 (m,
1H), 1.40–1.32 (m, 2H), 1.42 (d, J=6.7 Hz, 3H), 0.78 ppm (t, J=7.5 Hz,
3H); 13C NMR (100 MHz, CDCl3, 258C): d=202.8, 142.6, 130.2, 130.1,
124.0, 83.2, 52.5, 48.0, 20.6, 17.6, 10.1 ppm.
258C) at 0.5 mLminÀ1, UV detection at l=210 nm: t
(major)=26.3 min.
CHTUNGTRENNUNG
ACHTUNGTRENNUNG(2R,3S,4R)-2-Ethyl-4-nitro-3-(4-nitrophenyl)pentan-1-ol: Yellow oil;
1H NMR (400 MHz, CDCl3, 258C): d=8.16 (d, J=8.7 Hz, 2H), 7.37 (d,
J=8.7 Hz, 2H), 5.23 (dq, J=8.8, 6.6 Hz, 1H), 3.90 (dd, J=10.8, 3.9 Hz,
1H), 3.67 (dd, J=8.8, 6.0 Hz, 1H), 3.26 (dd, J=10.8, 8.1 Hz, 1H), 2.08–
1.96 (m, 1H), 1.62 (d, J=6.6 Hz, 3H), 1.38–1.22 (m, 1H), 1.07–0.94 (m,
1H), 0.91 ppm (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3, 258C):
d=147.5, 144.5, 130.3, 123.6, 84.6, 61.5, 49.9, 42.8, 20.2, 18.5, 12.4 ppm; el-
emental analysis calcd (%) for C13H18N2O5: C 55.31, H 6.43, N 9.92;
found: C 55.19, H 6.66, N 9.70; the enantiomeric excess was determined
by HPLC by using a Chiracel AS-H column (n-hexane/iPrOH 92.5:7.5,
Yellow oil; 1H NMR (400 MHz, CDCl3, 258C): d=9.87 (d, J=1.2 Hz,
1H), 8.26–8.20 (m, 2H), 7.35–7.21 (m, 5H), 7.15–7.09 (m, 2H), 5.31 (dt,
J=9.7, 5.0 Hz, 1H), 3.69 (dd, J=10.4, 5.0 Hz, 1H), 3.26–3.18 (m, 1H),
3.00 (dd, J=14.6, 9.7 Hz, 1H), 2.93 (dd, J=14.6, 5.0 Hz, 1H), 1.60 (ddd,
J=14.7, 7.5, 3.4 Hz, 1H), 1.41–1.29 (m, 1H), 0.76 ppm (t, J=7.5 Hz,
3H); 13C NMR (100 MHz, CDCl3, 258C): d=202.7, 148.1, 142.4, 135.0,
130.3, 129.1, 128.9, 127.7, 124.0, 89.1, 52.3, 46.7, 37.7, 20.7, 9.8 ppm.
258C) at 0.5 mLminÀ1, UV detection at l=210 nm: t
(major)=52.9 min.
RACHTUNGTREN(NUNG minor)=50.9,
AHCTUNGTERG(NNUN 2R,3S,4R)-2-Ethyl-4-nitro-3-(4-nitrophenyl)-5-phenylpentan-1-ol:
Yellow oil; 1H NMR (400 MHz, CDCl3, 258C): d=8.24–8.09 (m, 2H),
7.44–7.35 (m, 2H), 7.35–7.22 (m, 3H), 7.22–7.11 (m, 2H), 5.39 (ddd, J=
9.8, 8.2, 4.5 Hz, 1H), 3.97 (dd, J=10.8, 3.8 Hz, 1H), 3.77 (dd, J=8.2,
6.9 Hz, 1H), 3.35 (dd, J=10.8, 7.3 Hz, 1H), 3.22 (dd, J=14.5, 4.4 Hz,
1H), 3.14 (dd, J=14.5, 9.9 Hz, 1H), 2.18–2.06 (m, 1H), 1.44–1.27 (m,
1H), 1.17–0.98 (m, 1H), 0.91 ppm (t, J=7.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3, 258C): d=147.6, 144.2, 135.3, 130.4, 129.1, 128.9,
127.8, 123.6, 90.9, 61.4, 49.4, 42.9, 38.5, 20.6, 12.4 ppm; elemental analysis
calcd (%) for C19H22N2O5: C 63.68, H 6.19, N 7.82; found: C 63.41, H
6.36, N 7.47; the enantiomeric excess was determined by HPLC by using
ACHTUNGTRENNUNG(2R,3S,4R)-3-(2,4-Dichlorophenyl)-2-ethyl-4-nitropentanal (3g): Color-
less oil; 1H NMR (400 MHz, CDCl3, 258C): d=9.88 (d, J=1.5 Hz, 1H),
7.46 (d, J=2.2 Hz, 1H), 7.24 (dd, J=8.5, 2.2 Hz, 1H), 6.91 (d, J=8.5 Hz,
1H), 5.15–5.04 (m, 1H), 4.15 (dd, J=10.6, 4.8 Hz, 1H), 3.26–3.14 (m,
1H), 1.59–1.49 (m, 1H), 1.40 (d, J=6.7 Hz, 3H), 1.38–1.30 (m, 1H),
0.76 ppm (t, J=7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3, 258C): d=
202.9, 136.3, 134.7, 132.0, 130.0, 127.9, 83.3, 52.9, 42.2, 20.7, 16.7, 9.9 ppm.
ACHTUNGTRENNUNG(2R,3S,4R)-3-(2,4-Dichlorophenyl)-2-ethyl-4-nitropentan-1-ol: Colorless
oil; 1H NMR (400 MHz, CDCl3, 258C): d=7.43 (d, J=2.2 Hz, 1H), 7.21
(dd, J=8.5, 2.2 Hz, 1H), 7.05 (d, J=8.5 Hz, 1H), 5.20 (p, J=6.7 Hz, 1H),
4.06–3.94 (m, 2H), 3.70 (dd, J=11.5, 5.0 Hz, 1H), 1.98 (ddt, J=12.7, 8.6,
4.3 Hz, 1H), 1.52 (d, J=6.7 Hz, 3H), 1.22–1.09 (m, 2H), 0.86 ppm (t, J=
7.4 Hz, 4H); 13C NMR (100 MHz, CDCl3, 258C): d=136.5, 134.0, 133.9,
129.8, 127.6, 84.0, 61.6, 45.4, 43.4, 21.3, 17.7, 12.0 ppm; elemental analysis
calcd (%) for C13H17NCl2O3: C 51.00, H 5.60, N 4.57; found: C 51.04, H
5.79, N 4.55; the enantiomeric excess was determined by HPLC by using
a Chiracel AS-H column (n-hexane/iPrOH 90:10, 258C) at 0.5 mLminÀ1
UV detection at l=210 nm: tRA(minor)=36.4, (major)=40.3 min.
,
CTHUNGTRENNUNG
(R)-2-((1R,2R)-2-Nitrocyclohexyl)butanal (3k): Colorless oil; 1H NMR
(400 MHz, CDCl3, 258C): d=9.68 (d, J=1.6 Hz, 1H), 4.87 (q, J=3.4 Hz,
1H), 2.50 (dddd, J=9.7, 8.0, 3.7, 1.6 Hz, 1H), 2.32–2.23 (m, 1H), 2.17–
2.06 (m, 1H), 1.92–1.52 (m, 7H), 1.44–1.16 (m, 2H), 0.84 ppm (t, J=
7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3, 258C): d=203.6, 83.5, 53.1,
37.3, 29.6, 25.0, 23.2, 20.1, 19.3, 9.9 ppm.
a
Chiracel AS-H column (n-hexane/iPrOH 97.5:2.5, 258C) at
1118
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ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 1111 – 1120

Peptides as Catalysts for Conjugate Addition Reactions
FULL PAPER
(R)-2-((1R,2R)-2-nitrocyclohexyl)butan-1-ol: Colorless oil; 1H NMR
(400 MHz, CDCl3, 258C): d=5.00–4.92 (m, 1H), 3.68 (dd, J=11.2,
3.8 Hz, 1H), 3.64 (dd, J=11.2, 4.3 Hz, 1H), 2.35–2.25 (m, 1H), 1.93–1.00
(m, 11H), 0.87 ppm (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3,
258C): d=84.4, 61.6, 43.0, 40.3, 31.0, 25.4, 23.5, 20.8, 20.3, 11.4 ppm; ele-
mental analysis calcd (%) for C10H19NO3: C 59.68, H 9.51, N 6.96; found:
C 59.58, H 9.41, N 6.81; the enantiomeric excess was determined by
HPLC by using a Chiracel AS-H column (n-hexane/iPrOH 94:6, 258C)
Trombini, Adv. Synth. Catal. 2009, 351, 2801–2806; u) H. Uehara,
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RACTHNUTRGENUG(N minor)=18.7, (major)=
20.8 min.
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Acknowledgements
We thank Dr. Markus Neuburger for help with the crystal structure anal-
ysis and Stephan Steinmann for the ab initio calculations. This work was
supported by BACHEM and the Swiss National Science Foundation. We
thank the EU for support by the Research Training Network REVCAT.
H.W. is grateful to BACHEM for an endowed professorship.
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1119

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in the presence of 1.2 equivalents of NEt3 epimerization at the
carbon atom bearing the nitro group was observed. At equilibrium,
a ratio of 1:2.4 in favor of the newly formed epimer was obtained,
which is comparable to the ratio of the epimers formed in the pres-
ence of pyrrolidine.
[22] Interestingly, this is the same main stereoisomer that was obtained
by Seebach and co-workers in the conjugate addition reaction be-
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2b followed by diastereoselective protonation: M. Brenner, D. See-
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Received: August 10, 2011
Published online: December 21, 2011
1120
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Chem. Eur. J. 2012, 18, 1111 – 1120