Tripeptides of the type H-D-Pro-Pro-Xaa-NH2 as catalysts for asymmetric 1,4-addition reactions: structural requirements for high catalytic efficiency

Article abstract of DOI:10.1002/chem.200901021

Analysis of the structural and functional requirements within the asymmetric peptidic catalyst H-D-ProPro-Asp-NH₂ led to the development of the closely related peptide H-D-ProPrO-Glu-NH₂ as an even more efficient catalyst for asymmet

Full text of DOI:10.1002/chem.200901021

FULL PAPER
DOI: 10.1002/chem.200901021
Tripeptides of the Type H-d-Pro-Pro-Xaa-NH2 as Catalysts for Asymmetric
1,4-Addition Reactions: Structural Requirements for High Catalytic
AHCTUNGTRENNGEUN fficiency
Markus Wiesner,[a] Markus Neuburger,[b] and Helma Wennemers*[a]
Abstract: Analysis of the structural
fins react readily with each other. The
resulting g-nitroaldehydes were ob-
tained in excellent yields and stereose-
lectivities at room temperature. Within
the structure of the peptidic catalysts,
the d-Pro-Pro motif is the major con-
and functional requirements within the
asymmetric peptidic catalyst H-d-Pro-
Pro-Asp-NH2 led to the development
of the closely related peptide H-d-Pro-
Pro-Glu-NH2 as an even more efficient
catalyst for asymmetric conjugate addi-
tion reactions of aldehydes to nitroole-
fins. In the presence of as little as
1 mol% of H-d-Pro-Pro-Glu-NH2, a
broad range of aldehydes and nitroole-
tributor to the high stereoselectivities.
The C-terminal amide and the spacer
to the carboxylic acid in the side-chain
of the C-terminal amino acid are re-
sponsible for the fine-tuning of the ste-
reoselectivity. The peptidic catalysts
not only allow for highly effective
asymmetric catalysis under mild condi-
tions, but also function in the absence
of additives.
Keywords: asymmetric catalysis
·
conformation analysis · conjugate
addition reactions
proline
·
peptides
·
Introduction
react readily to provide the g-nitroaldehydes in excellent
yields and stereoselectivities (Scheme 1). In addition, only a
small excess of the aldehyde (3 equiv) with respect to the ni-
troolefin is required. This is in contrast to many of the other
amine-based catalysts that typically require the use of high
catalyst loadings (10–20 mol%), high excess of the aldehyde
(up to 10 equiv), and have often limited substrate scope.[3,5,8]
Conjugate addition reactions between aldehydes and nitro-
olefins are among the most useful asymmetric C C-bond
À
G
forming reactions.[1] The resulting g-nitroaldehydes are ver-
satile building blocks for further transformations into, for
example, chiral pyrrolidines, g-butyrolactones, g-amino
acids, or tetrahydropyrans.[1–4] As a result, several research
groups focused on the development of efficient catalysts for
this asymmetric reaction and explored a range of different
primary and secondary amine-based catalysts.[2–7] Recently,
our group introduced the peptide H-d-Pro-Pro-Asp-NH2, 1
as a highly effective catalyst for conjugate addition reactions
of aldehydes to b-substituted nitroolefins.[7] In the presence
of as little as 1 mol% of the peptidic catalyst 1 a broad
range of different aldehydes and b-substituted nitroolefins
Scheme 1. Conjugate addition reactions of aldehydes to nitroolefins cata-
lyzed by peptide 1.
[a] Dr. M. Wiesner, Prof. Dr. H. Wennemers
Department of Chemistry, University of Basel
St. Johanns-Ring 19, 4056 Basel (Switzerland)
Fax : (+41)61-267-0976
Additional attractive features of peptidic catalysts[9,10] in
general are their modular nature; allowing for facile varia-
tions of their structural and functional properties as well as
the ease of peptide synthesis by standard solid-phase synthe-
sis. With this in mind we decided to investigate the structur-
al and functional requirements necessary for effective catal-
ysis with peptide 1 and at the same time seek an even better
E-mail: Helma.Wennemers@unibas.ch
[b] M. Neuburger
Department of Chemistry, University of Basel
Spitalstrasse 51, 4056 Basel (Switzerland)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901021.
Chem. Eur. J. 2009, 15, 10103 – 10109
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
10103

catalyst for conjugate addition reactions of aldehydes to
b-substituted nitroolefins.
conformation of catalysts. We were therefore pleased to
obtain crystals of peptide 1 that were suitable for X-ray
single-crystal structure analysis. In the solid state, peptide 1
adopts a b-turn structure as indicated by a hydrogen bond
(H-bond) formed between the d-Pro-Pro amide bond and
the C-terminal carboxamide (Figure 1).[12] This conformation
is rather compact, suggesting that packing effects within the
solid state could favor this b-turn structure.
Previous studies had revealed that the d-Pro-Pro motive
as a turn-inducing element is important for high catalytic ef-
ficiency.[7] In addition, control experiments with N-terminal-
ly acetylated and methylated peptides showed the impor-
tance of the secondary amine for catalytic activity.[7,11] In-
spired by a crystal structure of peptide 1, we discuss within
this manuscript the role of the functional group at the C ter-
minus for effective catalysis. Furthermore, we evaluated the
importance of the carboxylic acid as well as the spacer
length between the peptidic backbone and the carboxylic
acid. Finally we explored whether additives (acids or bases)
that are known to affect the reactivity and stereoselectivity
of many secondary amine-based catalysts[3,4b,5] also influence
the catalytic performance of the peptidic catalysts. The re-
search revealed that the closely related peptide H-d-Pro-
Pro-Glu-NH2, 2, that had previously been identified as an
effective catalyst for asymmetric addition reactions of alde-
hydes to nitroethylene,[4a] is also best suited for catalyzing
conjugate addition reactions of aldehydes to a broad range
of b-substituted nitroolefins. Both the catalytic reactivity
and stereoselectivity of peptide 2 are even better compared
to those of the parent peptide 1. In addition, the work dem-
onstrates that the peptidic catalysts do not require any addi-
tives for effective catalysis.
Figure 1. Crystal structure and schematic of H-d-Pro-Pro-Asp-NH2 (1).
To evaluate the importance of the C-terminal amide for
the catalytic efficiency of peptide 1 in the solution phase, we
prepared closely related peptides that differ in the C-termi-
nal functional groups. Within the structures of peptides H-d-
Pro-Pro-b-Ala-OH, 3, and H-d-Pro-Pro-Asp-OCH3, 4, the
C-terminal carboxamide is replaced by functional groups
(hydrogen and methyl ester, respectively) that are not able
to function as H-bond donors (Table 1). Peptides H-d-Pro-
Pro-Asp-OH, 5, and H-d-Pro-Pro-Asp-NHPr (Pr=n-
propyl), 6 bear carboxylic acid and secondary amide moiet-
ies, respectively, in place of the primary carboxamide, and in
peptide H-d-Pro-Pro-b-Asp-NH2, 7, an additional methylene
Results and Discussion
Crystal structure of H-d-Pro-Pro-Asp-NH2 (1)—is a b-turn
conformation important for effective catalysis? Crystal
structures can provide important insight into the preferred
group is introduced as
a spacer to the carboxamide
(Table 1). To analyze the catalytic properties of peptides 3–7
the conjugate addition reaction between butanal and nitro-
styrene served as a test reaction by using conditions that
were previously found to be optimal for catalysis.[7] These
involve the use of 1 mol% of the peptidic catalyst and 3
equivalents of butanal with respect to nitrostyrene in a mix-
ture of CHCl3/iPrOH 9:1.
With all of the peptidic catalysts good to very good con-
versions and stereoselectivities of the g-nitroaldehyde (syn/
anti ꢀ19:1, ꢀ85% ee) were observed (Table 1, entries 2–6).
However, none of the peptides performed as well as the
parent catalyst H-d-Pro-Pro-Asp-NH2 (1) (syn/anti 25:1,
95% ee, Table 1, entry 1). This demonstrates that peptides
that cannot be stabilized by an intramolecular H-bond to
form a b turn and lack the stereogenic center of the C-termi-
nal amino acid (as in 3) are also reasonable asymmetric cat-
alysts. At the same time, the results revealed that both the
presence and the position of the C-terminal primary carbox-
amide are crucial for highly efficient asymmetric catalysis.
Thus, the main contribution for the excellent asymmetric in-
duction and catalytic activity of peptide 1 stems from the d-
Pro-Pro portion, whereas the C-terminal amide is important
for the fine-tuning of the stereoselectivity.
Abstract in German: Die sorgfꢀltige Analyse der strukturel-
ACHTUNGTRENNUNGlen und funktionalen Erfordernisse des peptidischen Kataly-
sators H-d-Pro-Pro-Asp-NH2 fꢁhrte zur Entwicklung des
verwandten Peptids H-d-Pro-Pro-Glu-NH2, das einen noch
effizienteren Katalysator fꢁr asymmetrische konjugierte Ad-
ditionsreaktionen von Aldehyden an Nitroolefine darstellt. In
Gegenwart von nur 1 mol% von H-d-Pro-Pro-Glu-NH2 rea-
giert eine große Auswahl verschiedenster Aldehyde und Ni-
troolefine unter milden Bedingungen bereitwillig miteinander.
Die entstehenden g-Nitroaldehyde bilden sich in exzellenten
Ausbeuten und Stereoselektivitꢀten bei Raumtemperatur. In-
nerhalb der Struktur des peptidischen Katalysators trꢀgt das
d-Pro-Pro Motiv am meisten zu den hohen Stereoselektivitꢀt-
en bei. Das C-terminale Amid und der Linker vom Peptid-
rꢁckgrat zur Carbonsꢀure in der Seitenkette der C-terminalen
Aminosꢀure sind fꢁr die Feineinstellung der Stereoselektivi-
tꢀten verantwortlich. Die peptidischen Katalysatoren sind
nicht nur hçchst effiziente asymmetrische Katalysatoren son-
dern bençtigen im Gegensatz zu vielen anderen chiralen Ka-
talysatoren auch keine Additive fꢁr ihre katalytische Effi-
zienz.
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Asymmetric 1,4-Addition Reactions
FULL PAPER
Table 1. Conjugate addition reactions catalyzed by peptides 3–7 differing
in the functional group at the C terminus.
Next we tested the influence of the spacer from the pepti-
dic backbone to the carboxylic acid in the side-chain of the
C-terminal amino acid on the catalytic efficiency. Toward
this goal we compared H-d-Pro-Pro-Asp-NH2, 1 with the
peptides H-d-Pro-Pro-Glu-NH2, 2, H-d-Pro-Pro-Aad-NH2,
10 (Aad=a-amino adipic acid), H-d-Pro-Pro-Api-NH2, 11
(Api=a-amino pimelic acid) and H-d-Pro-Pro-Asu-NH2, 12
(Asu=a-amino suberic acid); these compounds bear up to
four additional methylene groups as spacers between the
backbone and the carboxylic acid. Remarkably, the glutamic
acid analogue 2 with an additional methylene group in the
side-chain proved to be an even better catalyst than 1. The
g-nitroaldehyde was obtained in almost perfect diastereose-
lectivity (syn/anti 50:1) and excellent enantioselectivity of
97% ee (Table 2, entry 4). Peptide 10 with one more addi-
tional methylene group in the spacer is still a very good cat-
alyst with an efficiency that is comparable to that of the
parent peptide 1 (Table 2, entry 5). Even peptides 11 and 12
with more flexible spacers exhibit reasonable catalytic effi-
ciencies (Table 2, entries 6 and 7). These findings demon-
strate that a considerable degree of conformational flexibili-
ty is tolerated in the side-chain of the C-terminal amino
acid. In addition, they further underline that the d-Pro-Pro
motif is the major contributor to the high asymmetric induc-
tion of peptidic catalysts of the type H-d-Pro-Pro-Xaa-NH2
in which Xaa is an amino acid with a carboxylic acid in the
side-chain.
Entry
X
Catalyst
Conv. [%][a]
syn/anti[a]
ee [%][b]
1
2
3
4
5
6
CONH2
H
CO2CH3
CO2H
CONHPr
CH2CONH2
1
1
3
4
5
6
7
95
80
95
80
85
95
25:1
26:1
30:1
21:1
23:1
19:1
95
88
89
85
92
85
[a] Determined by H NMR spectroscopy of the reaction mixture. [b] De-
termined by chiral-phase HPLC analysis.
Importance of functional groups and the spacer length in
the side-chain of the C-terminal amino acid: To evaluate the
importance of the carboxylic acid within the structure of H-
d-Pro-Pro-Asp-NH2,
NH2, 8 and H-d-Pro-Pro-AspAHCTNUGTRENNNUG
1
the analogues H-d-Pro-Pro-Asn-
(OtBu)-NH2, 9 with amide and
ester moieties, respectively, in place of the carboxylic acid
were prepared. Both peptides proved to be significantly
poorer catalysts compared to 1, both with respect to their
catalytic activities and stereoselectivities (Table 2, entries 1–
3). Thus, not only the secondary amine but also the carbox-
ylic acid is crucial for effective catalysis. This result suggests
that the carboxylic acid plays a crucial role in coordinating
and thereby orienting the nitroolefin into a position that
allows for the excellent stereochemical induction that is ob-
served for peptidic catalyst 1.[13]
Substrate scope of peptidic catalyst H-d-Pro-Pro-Glu-NH2
(2) in 1,4-addition reactions between aldehydes and nitro-
AHCTUNGTREGoNNUN lefins: A careful comparison of the catalytic efficiencies of
peptides 1 and 2 demonstrated that both the catalytic activi-
ty and stereoselectivity of peptide 2 are higher compared to
those of 1. Under the same conditions (3 equiv butanal,
1 equiv nitrostyrene), the conjugate addition reaction of
butanal to nitrostyrene is complete within 8 h with 2, where-
as 12 h are required with 1. This higher reactivity of 2 al-
lowed us to further reduce the excess of aldehyde with re-
spect to the nitroolefin, which is required for good reaction
yields. By using as little as 1.5 equivalents of the aldehyde,
the conjugate addition product was obtained in the same
high enantioselectivity (97% ee) and only slightly lower dia-
stereoselectivity (syn/anti 42:1) within a slightly longer reac-
tion time under otherwise identical conditions (Table 3,
entry 1). These improved conditions were used to evaluate
the substrate scope of catalyst 2.
Table 2. Conjugate addition reactions catalyzed by peptides 1, 2, and 8–
10 differing in the side-chain of the C-terminal amino acid.
In the presence of 1 mol% of 2 a range of aldehyde and
nitroolefin combinations reacted readily with each other.
The resulting g-nitroaldehydes were obtained in excellent
yields and stereoselectivities within 12–24 h at room temper-
ature (Table 3). Aromatic nitroolefins bearing both electron-
poor and electron-rich aromatic substituents (Table 3, en-
tries 6–8) as well as aliphatic nitroolefins (Table 3, entries 9
and 10) react readily with aromatic as well as linear or b-
branched aliphatic aldehydes (Table 3, entries 1–10). The
best results were obtained with nitroolefins bearing elec-
tron-poor aromatic substituents (e.g. Table 3, entry 7), how-
Entry
Y
Catalyst Conv. [%][a] syn/anti[a] ee [%][b]
1
CO2H
CONH2
CO2tBu
CH2CO2H
CH2CH2CO2H
1
95
25:1
6:1
95
72
64
97
94
92
86
2[c]
3[d]
4
8
44
9
30
8:1
2
10
quant.
quant.
95
50:1
30:1
27:1
24:1
5
6
7
CH
CH
2A
2A(CH2)3CO2H 12
85
1
[a] Determined by H NMR spectroscopy of the reaction mixture. [b] De-
termined by chiral-phase HPLC analysis. [c] reaction time was 72 h.
[d] reaction time was 36 h.
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H. Wennemers et al.
Table 3. Substrate scope of conjugate addition reactions between alde-
hydes and nitroolefins catalyzed by peptide 2.
We also tested the catalytic efficiency of 2 in conjugate
addition reactions of different aldehydes with b-nitroacro-
leine dimethylacetal (Table 3, entries 11–13). This is a partic-
ularly interesting nitroolefin[3a,5m] because reactions with al-
dehydes bearing functional groups in their side-chains result
in highly functionalized g-nitroaldehydes that bear four dif-
ferent functional groups (Table 3, entry 13). Gratifyingly the
highly functionalized products formed not only in yields of
ꢀ95% but also with high diastereoselectivities (16:1 to
>99:1) and enantioselectivities (90–95%). These results
demonstrate that H-d-Pro-Pro-Glu-NH2 2 is an excellent
catalyst not only for aromatic and aliphatic but also func-
tionalized aldehydes and nitroolefins.
Entry Product
1
Yield[a] [%] syn/anti[b] ee[c] [%]
13a
13b
13c
13d
13e
13 f
13g
13h
13i
96
42:1
7:1
97
95
96
96
97
96
98
95
98
97
2
98
3
98
27:1
61:1
25:1
36:1
>99:1
21:1
6:1
Effect of additives on the catalytic efficiency of peptide 2:
The peptidic catalysts are easily prepared by solid-phase
peptide synthesis on Rink amide resin by using the 9H-fluo-
ren-9-ylmethoxycarbonyl (Fmoc)/tBu protocol and removed
from the acid-labile resin by using trifluoroacetic acid (TFA;
see supporting information for details). The resulting TFA
salts are isolated by simple precipitation from, for example,
diethyl ether, and can be easily prepared on a multigram
scale within a day. As a result, the addition of a base such as
N-methylmorpholine (NMM)[15] is necessary to liberate the
secondary amine and allow for catalysis. We were curious to
test whether the presence of TFA and NMM affects the cat-
alytic performance of the peptidic catalyst and investigated
whether the high catalytic efficiency of peptide 2 is also ach-
ieved in the absence of TFA and NMM. Thus, the TFA of
the peptide 2·TFA salt was removed by ion exchange chro-
matography, and the resulting “desalted peptide 2” was
tested for its catalytic efficiency in the test reaction of buta-
nal to nitrostyrene. In addition, we tested the effect of other
additives such as HCl/NMM, AcOH/NMM, NMM and TFA
on the catalytic activity of the “desalted peptidic catalyst”
(Table 4).
4[d]
93
5
94
6
97
7
95
8[d]
9[d]
10
quant.
84
13j
90
24:1
11[e]
12[d,e]
13[e]
13k
13l
quant.
95
68:1
92
95
90
Table 4. Effect of additives on the catalytic efficiency of peptide 2.
>99:1
16:1
Entry
Additive
Conv. [%][a]
syn/anti[a]
ee [%][b]
13m 95
1
2
3
4
TFA·NMM
none
AcOH·NMM
HCl·NMM
NMM
quant
quant
quant
quant
98
50:1
50:1
50:1
52:1
50:1
nd[d]
97
97
96
96
[a] Isolated yield. [b] Determined by 1H NMR spectroscopy of the reac-
tion mixture. [c] Determined by chiral-phase HPLC analysis. [d] Use of
2 mol% of catalyst and NMM. [e] Reactions were performed in pure
CHCl3.
5
97
6[c]
TFA
16
nd[d]
1
[a] Determined by H NMR spectroscopy of the reaction mixture. [b] De-
termined by chiral-phase HPLC analysis. [c] Reaction time of 72 h.
[d] Not determined.
ever, even with the poorest substrate combination (aliphatic
nitroolefin and propanal, entry 9) a diastereoselectivity of
6:1 and enantioselectivity of 98% ee was achieved. In com-
parison to 1 the improved catalyst 2 has generally an enan-
tioselectivity that is greater by 2–4% ee at room tempera-
ture.[14]
Remarkably, the “desalted peptide 2” performed equally
well as the TFA salt of 2 in the presence of NMM (Table 4,
entry 2). Furthermore, also the addition of HCl·NMM,
AcOH·NMM or NMM alone did not affect the excellent
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Asymmetric 1,4-Addition Reactions
FULL PAPER
their syntheses and analytical data of peptides 3–12, see the Supporting
Information.
catalytic efficiency of peptide 2 (entries 3–5). Only the addi-
tion of TFA to the desalted peptide reduced the catalytic ac-
tivity dramatically, further underlining that the secondary
amine is crucial for catalysis. These results demonstrate that
no additives are necessary for the high catalytic efficiency of
peptide 2. This is in contrast to many of the other amine-
based catalysts that require the addition of acids and/or
bases.[3,4b,5]
TFA·H-d-Pro-Pro-Glu-NH2 (2): 1H NMR (400 MHz, D2O, 25 8C): d=
4.51 (dd, J=7.1, 8.8 Hz, 1H), 4.34 (dd, J=3.6, 9.0 Hz, 1H), 4.23 (dd, J=
5.2, 9.5 Hz, 1H), 3.60 (m, 1H), 3.49 (m, 1H), 3.29 (m, 2H), 2.40 (m, 3H),
2.19 (m, 1H), 2.08–1.80 ppm (m, 8H); 13C NMR (100 MHz, D2O, 25 8C):
d=177.4, 176.2, 174.5, 168.6, 61.2, 59.6, 53.2, 48.0, 47.0, 30.3, 29.8, 28.5,
26.4, 24.7, 24.3 ppm; HRMS (ESI): m/z: calcd for C15H25N4O5 [M+H]+
341.1824; found, 341.1821.
General procedure for 1,4-addition reactions: N-Methylmorpholine
(5.0 mL, 44 mmol, 0.1 equiv) was dissolved in a mixture of CHCl3 and
iPrOH 9:1 or neat CHCl3 (10 mL). This solution (1 mL) was added to
the catalyst (2.0 mg, 4.40 mmol, 0.01 equiv) and the mixture was stirred
for 5 min. The nitroolefin (0.44 mmol, 1 equiv) and the aldehyde
(0.66 mmol, 1.5 equiv) were added, and the reaction mixture (homogene-
ous solution) was stirred at RT. The reaction progress was followed by
TLC. After consumption of the nitroolefin, the product was purified by
flash column chromatography on silica gel by eluting with a mixture of
pentanes and EtOAc. Collected fractions were concentrated in vacuo
and the product was dried under high vacuum.
Conclusions
Analysis of the structural and functional prerequisites for
high catalytic efficiency within the asymmetric peptidic cata-
lyst H-d-Pro-Pro-Asp-NH2 (1) led to the establishment of
the closely related peptide H-d-Pro-Pro-Glu-NH2 (2) as an
even more effective catalyst for conjugate addition reactions
between aldehydes and nitroolefins. Peptide 2, differing
from 1 only by one additional methylene group, is a both
more reactive and stereoselective catalyst. This allowed for
a further improvement of the reaction conditions: in the
presence of as little as 1 mol% of 2 and only 1.5 equivalents
of the aldehyde, a broad range of different aldehydes and
nitroolefins react readily at room temperature to provide
synthetically useful g-nitroaldehydes in excellent yields and
stereoselectivities. Additional attractive features of the pep-
tidic catalysts are their ease of synthesis and the fact that
they do not require additives for their excellent catalytic
performance but function equally as well in the presence of
salts such as TFA·NMM.
The work also provided insight into the structural and
functional features that render peptides of the type H-d-
Pro-Pro-Xaa-NH2 such efficient asymmetric catalysts:
1) Both the secondary amine and the carboxylic acid are
crucial for effective catalysis, 2) whereas the d-Pro-Pro
moiety is the basic contributor to high asymmetric induc-
tion, the C-terminal amide together with the distance of the
carboxylic acid from the peptide backbone are responsible
for the remarkably high stereoselectivities. Since the rational
design of catalysts, and peptidic catalysts in particular, is still
a tremendous challenge these insights provide important
design concepts for new catalysts.
AHCTUNGTERG(NNUN 2S,3R)-2-Ethyl-4-nitro-3-phenylbutanal (13a): The enantiomeric excess
was determined by HPLC by using a Chiracel AD-H column (n-hexane/
iPrOH 99.5:0.5, 258C) at 0.9 mLminÀ1, UV detection at 254 nm: tR (syn,
minor)=36.8 min, (syn, major)=47.9 min; colorless oil; 1H NMR
(400 MHz, CDCl3, 258C): d=9.72 (d, J=2.6 Hz, 1H), 7.32 (m, 3H), 7.18
(m, 2H), 4.72 (dd, J=5.0, 12.7 Hz, 1H), 4.63 (dd, J=9.7, 12.7 Hz, 1H),
3.79 (dt, J=5.0, 9.8 Hz, 1H), 2.68 (dddd, J=2.6, 5.0, 7.6, 10.1 Hz, 1H),
1.51 (m, 2H), 0.84 ppm (t, J=7.5 Hz); 13C NMR (100 MHz, CDCl3,
258C): d =203.1, 136.8, 129.1 (2), 128.1, 128.0 (2), 78.5, 55.0, 42.7, 20.4,
10.7 ppm (see also ref. [3g]); elemental analysis calcd (%) for C12H15NO3:
C 65.14, H 6.83, N 6.33; found: C 65.18, H 6.97, N 6.36.
AHCTUNGERTG(NNUN 2S,3R)-2-Methyl-4-nitro-3-phenylbutanal (13b): The enantiomeric
excess was determined by HPLC by using a Chiracel OD-H column (n-
hexane/iPrOH 90:10, 258C) at 1 mLminÀ1, UV detection at 254 nm: tR
(syn, major)=23.5 min, (syn, minor)=34.4 min; colorless oil; 1H NMR
(400 MHz, CDCl3, 258C): d=9.72 (d, J=1.7 Hz, 1H), 7.32 (m, 3H), 7.17
(m, 2H), 4.80 (dd, J=5.5, 12.7 Hz, 1H), 4.68 (dd, J=9.31, 12.7 Hz, 1H),
3.81 (dt, J=5.6, 9.2 Hz, 1H), 2.79 (m, 1H), 1.00 ppm (d, J=7.3 Hz, 3H);
13C NMR (100 MHz, CDCl3, 258C): d=202.2, 136.5, 129.1 (2), 128.1,
128.0 (2), 78.1, 48.4, 44.0, 12.1 (see also ref. [3g]); elemental analysis
calcd (%) for C11H13NO3: C 63.76, H 6.32, N 6.76; found: C 63.75, H
6.35, N 6.64.
AHCTUNGTERG(NNUN 2S,3R)-2-Butyl-4-nitro-3-phenylbutanal (13c): The enantiomeric excess
was determined by HPLC by using a Chiracel OD-H column (n-hexane/
iPrOH 80:20, 258C) at 1 mLminÀ1, UV detection at 254 nm: tR (syn,
major)=10.9 min, (syn, minor)=13.7 min; colorless oil; 1H NMR
(400 MHz, CDCl3, 258C): d=9.70 (d, J=2.8 Hz, 1H), 7.32 (m, 3H), 7.17
(m, 2H), 4.71 (dd, J=9.5, 12.8 Hz, 1H), 4.64 (dd, J=9.5, 12.8 Hz, 1H),
3.78 (dt, J=5.3, 9.6 Hz, 1H), 2.60 (m, 1H), 1.54–1.09 (m, 6H), 0.78 ppm
(t, J=7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3, 258C): d =203.2, 136.8,
129.1 (2), 128.1, 128.0 (2), 78.4, 53.9, 43.1, 28.5, 27.0, 22.5, 13.6 ppm (see
also ref. [3g]); elemental analysis calcd (%) for C14H19NO3: C 67.45, H
7.68, N 5.62, found: C 67.53, H 7.70, N 5.70.
AHCTUNGTERG(NNUN 2S,3R)-2-Isopropyl-4-nitro-3-phenylbutanal (13d): The enantiomeric
Experimental Section
excess was determined by HPLC by using a Chiracel AD-H column (n-
hexane/iPrOH 97:3, 258C) at 0.5 mLminÀ1, UV detection at 254 nm: tR
(syn, minor)=22.8 min, (syn, major)=26.6 min; colorless oil; 1H NMR
(400 MHz, CDCl3, 258C): d=9.93 (d, J=2.4 Hz, 1H), 7.32 (m, 3H), 7.19
(m, 2H), 4.67 (dd, J=4.4, 12.5 Hz, 1H), 4.57 (dd, J=10.0, 12.5 Hz, 1H),
3.90 (dt, J=4.4, 10.3 Hz, 1H), 2.77 (ddd, J=2.4, 4.1, 10.8 Hz, 1H), 1.72
(dsept., J=4.2, 7.1 Hz, 1H), 1.10 (d, J=7.2 Hz, 3H), 0.88 ppm (d, J=
7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3, 258C): d =204.3, 137.0, 129.1
(2), 128.1, 127.9 (2), 79.0, 58.7, 41.9, 27.9, 21.6, 16.9 ppm (see also
ref. [3g]); elemental analysis calcd (%) for C13H17NO3: C 66.36, H 7.28, N
5.95; found: C 66.44, H 7.16, N 6.07.
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 under UV light and
with KMnO4. Flash chromatography was performed by using Merck
silica gel 60, particle size 40–63 mm. 1H and 13C NMR spectra were re-
corded on a Bruker DPX 400 spectrometer. Chemical shifts are reported
in ppm by using the residual solvent peak or tetramethylsilane as a refer-
ence. HPLC analyses were performed on an analytical instrument with a
diode array detector from Shimadzu.
AHCTUNGTERG(NNUN 2S,3R)-2-Benzyl-4-nitro-3-phenylbutanal (13e): The enantiomeric excess
The peptidic catalysts were prepared by solid and solution-phase peptide
synthesis by following the standard Fmoc/tBu-protocol. For details on
was determined by HPLC by using a Chiracel AD-H column (n-hexane/
iPrOH 97.5:2.5, 258C) at 1 mLminÀ1, UV detection at 254 nm: tR (syn,
Chem. Eur. J. 2009, 15, 10103 – 10109
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10107

H. Wennemers et al.
minor)=21.9 min, (syn, major)=25.1 min; pale-yellow oil; 1H NMR
(400 MHz, CDCl3, 258C): d=9.64 (d, J=2.3 Hz, 1H), 7.33–7.11 (m, 8H),
6.95 (m, 2H), 4.65 (m, 2H), 3.76 (dt, J=6.1, 8.7 Hz, 1H), 3.04 (ddt, J=
2.3, 6.0, 8.6 Hz, 1H), 2.69 ppm (m, 2H); 13C NMR (100 MHz, CDCl3,
258C): d=203.0, 137.1, 136.6, 129.3 (2), 128.8 (2), 128.7 (2), 128.3, 128.0
(2), 126.9, 78.0, 55.3, 43.5, 34.3 ppm; elemental analysis calcd (%) for
C17H17NO3: C 72.07, H 6.05, N 4.94; found: C 72.09, H 6.02, N 4.70.
258C) at 0.5 mLminÀ1
24.1 min, (syn,
,
UV detection at 210 nm: tR (syn, major)=
minor)=26.4 min,
colorless
oil;
1H NMR
(400 MHz,CDCl3, 258C): d=9.64 (d, J=1.4 Hz, 1H), 4.61 (dd, J=7.2,
13.7 Hz, 1H), 4.37 (m, 2H), 3.38 (s, 3H), 3.36 (s, 3H), 3.04 (m, 1H), 2.55
(s, 1H), 1.82 (m, 1H), 1.49 (m, 1H), 1.03 ppm (t, J=7.4 Hz, 3H);
13C NMR (100 MHz, CDCl3, 258C): d=202.6, 104.4, 73.3, 55.3, 55.3, 51.3,
41.1, 19.5, 12.4 ppm (see also ref. [3k]); elemental analysis calcd (%) for
C9H17NO5: C 49.31, H 7.82, N 6.39; found: C 49.29, H 7.56, N 6.26.
ACHTUNGTRENNUNG(2S,3R)-3-(2,4-Dichlorophenyl)-2-ethyl-4-nitrobutyraldehyde (13 f): The
AHCTUNGTERG(NNUN 2S,3S)-2-Isopropyl-4,4-dimethoxy-3-(nitromethyl)butanal (13l): Reaction
was performed in neat CHCl3. The enantiomeric excess was determined
enantiomeric excess was determined by HPLC by using a Chiracel AD-
H column (n-hexane/iPrOH 98.5:1.5, 258C) at 1 mLminÀ1, UV detection
at 254 nm: tR (syn, minor)=18.0 min, (syn, major)=20.0 min; see also
ref. [7]; colorless oil; 1H NMR (400 MHz, CDCl3, 258C): d =9.73 (d, J=
2.1 Hz, 1H), 7.44 (d, J=2.1 Hz, 1H), 7.27 (m, 1H), 7.17 (d, J=8.5 Hz,
1H), 4.85 (dd, J=9.2, 13.0 Hz, 1H), 4.68 (dd, J=4.5, 13.0 Hz, 1H), 4.30
(dt, J=4.4, 9.5 Hz, 1H), 2.94 (m, 1H), 1.57 (m, 2H), 0.88 ppm (t, J=
7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3, 258C): d =202.4, 135.0, 134.5,
133.1, 130.3, 127.8 (2), 76.5, 53.7, 38.7, 20.4, 10.6 ppm; elemental analysis
calcd (%) for C12H13Cl2NO3: C 49.68, H 4.52, N 4.83; found: C 49.65, H
4.55, N 4.81.
by HPLC by using a Chiracel AS-H column (n-hexane/iPrOH 99:1,
258C) at 0.8 mLminÀ1
,
UV detection at 210 nm: tR (syn, major)=
19.1 min,
(syn,
minor)=22.8 min; colorless oil;
1H NMR
(400 MHz,CDCl3, 258C): d=9.75 (dd, J=0.5, 2.5 Hz, 1H), 4.61 (dd, J=
8.9, 14.0 Hz, 1H), 4.42 (dd, J=3.0, 14.0 Hz, 1H), 4.32 (d, J=4.6 Hz, 1H),
3.38 (s, 3H), 3.38 (s, 3H), 3.04 (m, 1H), 2.61 (ddd, J=2.6, 3.9, 9.0 Hz,
1H), 2.03 (septd, J=6.7, 8.7 Hz, 1H), 1.08 (d, J=6.8 Hz, 3H), 1.03 ppm
(d, J=6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3, 258C): d=204.3, 105.3,
73.0, 56.0, 55.4 (2), 40.2, 27.2, 20.9, 20.8 ppm (see also ref. [3k]); elemen-
tal analysis calcd (%) for C10H19NO5: C 51.49, H 8.21, N 6.00; found: C
51.52, H 8.10, N 6.00.
ACHTUNGTRENNUNG(2S,3R)-2-Ethyl-4-nitro-3-(2-trifluoromethylphenyl)butanal (13g): The
enantiomeric excess was determined by HPLC by using a Chiracel AD-
H column (n-hexane/iPrOH 99:1, 258C) at 0.8 mLminÀ1, UV detection at
254 nm: tR (syn, minor)=19.5 min, (syn, major)=21.6 min; colorless oil;
1H NMR (400 MHz, CDCl3, 258C): d=9.77 (dd, J=1.7, 2.8 Hz, 1H), 7.73
(d, J=7.9 Hz, 1H), 7.58 (t, J=7.7 Hz, 1H), 7.43 (t, J=7.6 Hz, 1H), 7.35
(d, J=7.8 Hz, 1H), 4.81 (ddd, J=1.4, 7.2, 12.6 Hz, 1H), 4.63 (ddd, J=
1.5, 4.9, 12.6 Hz, 1H), 4.17 (m, 1H), 2.91 (m, 1H), 1.60 (m, 1H), 1.38 (m,
1H), 0.87 ppm (dt, J=1.5, 7.7 Hz, 3H); 13C NMR (100 MHz, CDCl3,
258C): d=203.0, 136.2, 132.6, 128.2 (2), 128.1, 126.9, 126.9, 77.9, 55.5,
38.2, 21.3, 11.3 ppm (see also ref. [3f]); elemental analysis calcd (%) for
C13H14F3NO3: C 53.98, H 4.88, N 4.84; found: C 53.99, H 4.90, N 4.72.
AHCTUNGERTG(NNUN 3S,4S)-Methyl-3-formyl-5,5-dimethoxy-4-(nitromethyl)pentanoate
(13m): Reaction was performed in neat CHCl3. The enantiomeric excess
was determined by HPLC by using a Chiracel AD-H column (n-hexane/
iPrOH 97.5:2.5, 258C) at 0.5 mLminÀ1, UV detection at 210 nm: tR (syn,
minor)=57.2 min, (syn, major)=75.4 min; colorless oil; 1H NMR
(400 MHz,CDCl3, 258C): d=9.66 (s, 1H), 4.57 (dd, J=6.7, 13.9 Hz, 1H),
4.41 (dd, J=6.5, 13.9 Hz, 1H), 4.33 (d, J=5.1 Hz, 1H), 3.71 (s, 3H), 3.39
(s, 3H), 3.38 (s, 3H), 3.23 (ddt, J=3.3, 5.2, 6.6 Hz, 1H), 3.09 (m, 1H),
2.87 (dd, J=8.20, 17.22 Hz, 1H), 2.48 ppm (dd, J=5.21, 17.22 Hz, 1H);
13C NMR (100 MHz, CDCl3, 258C): d=200.1, 172.0, 104.3, 73.4, 56.3,
55.4, 52.2, 45.7, 40.7, 30.5 ppm; elemental analysis calcd (%) for
C10H17NO7: C 45.63, H 6.51, N 5.32; found: C 45.90, H 6.40, N 5.40.
ACHTUNGTRENNUNG(2S,3R)-2Ethyl-4-nitro-3-(4-methoxyphenyl)butanal (13h): The enantio-
meric excess was determined by HPLC by using a Chiral AM column (n-
hexane/iPrOH 99.6:0.4, 258C) at 1.2 mLminÀ1, UV detection at 254 nm:
tR (syn, minor)=52.2 min, (syn, major)=77.2 min; pale-yellow oil;
1H NMR (400 MHz,CDCl3, 258C): d=9.71 (d, J=2.7 Hz, 1H), 7.09 (m,
2H), 6.87 (m, 2H), 4.69 (dd, J=5.0, 12.5 Hz, 1H), 4.58 (dd, J=9.8,
12.5 Hz, 1H), 3.79 (s, 3H), 3.47 (dt, J=5.0, 9.9 Hz, 1H), 2.63 (m, 1H),
1.51 (m, 2H), 0.83 (t, J=7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3,
258C): d=203.3, 159.2, 129.0 (2), 128.5, 114.5 (2), 78.8, 55.2, 55.2, 42.0,
20.3, 10.7 ppm (see also ref. [3f]); elemental analysis calcd (%) for
C13H17NO4: C 62.17, H 6.82, N 5.57; found: C 61.85, H 6.68, N 5.47.
Acknowledgements
This work was supported by BACHEM and the Swiss National Science
Foundation. We thank the EU for support by the Research Training Net-
work REVCAT. H.W. is grateful to BACHEM for an endowed professor-
ship.
ACHTUNGTRENNUNG(2S,3S)-3-Cylohexyl-2-methyl-4-nitrobutanal (13i): 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 210 nm: tR
= (syn, major)=18.4 min, (syn, minor)=19.6 min; colorless oil; H NMR
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1
(400 MHz, CDCl3, 258C): d=9.69 (d, J=0.8 Hz, 1H), 4.59 (dd, J=5.4,
13.3 Hz, 1H), 4.39 (dd, J=6.8, 13.3 Hz, 1H), 2.77–2.54 (m, 2H), 1.81–
1.50 (m, 5H), 1.41 (m, 1H), 1.27–0.93 (m, 5H), 1.20 ppm (d, J=7.0 Hz,
3H); 13C NMR (100 MHz, CDCl3, 258C): d=203.1, 75.8, 46.6, 43.5, 38.0,
31.6, 30.0, 26.4, 26.2, 26.0, 10.7 ppm (see also ref. [3f]); elemental analysis
calcd (%) for C11H19NO3: C 61.95, H 8.98, N 6.57; found: C 61.92, H
8.81, N 6.53.
ACHTUNGTRENNUNG
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oil; 1H NMR (400 MHz, CDCl3, 258C): d=9.72 (d, J=1.3 Hz, 1H), 4.47
(dd, J=6.4, 12.5 Hz, 1H), 4.42 (dd, J=6.6, 12.5 Hz, 1H), 2.73 (m, 1H),
2.43 (dtd, J=1.3, 4.7, 6.0 Hz, 1H), 1.80 (m, 1H), 1.61 (m, 1H), 1.50 (dqd,
J=4.9, 7.4, 14.8 Hz, 1H), 1.24 (m, 2H), 1.01 (t, J=7.4 Hz, 3H), 0.92 (d,
J=4.9, 3H), 0.90 ppm (d, J=4.9 Hz, 3H); 13C NMR (100 MHz, CDCl3,
258C): d=203.0, 77.1, 54.0, 38.3, 34.7, 25.2, 22.7, 22.0, 18.5, 12.2 ppm; ele-
mental analysis calcd (%) for C10H19NO3: C 59.68; H 9.51; N 6.96; found:
C 59.83; H 9.26; N 6.80.
ACHTUNGTRENNUNG(2S,3S)-2-Ethyl-4,4-dimethoxy-3-(nitromethyl)butanal (13k): Reaction
was performed in neat CHCl3. The enantiomeric excess was determined
by HPLC by using a Chiracel AS-H column (n-hexane/iPrOH 95:5,
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10108
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Chem. Eur. J. 2009, 15, 10103 – 10109

Asymmetric 1,4-Addition Reactions
FULL PAPER
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[14] The stereoselectivities observed for peptide 2 at RT are comparable
to those observed for peptide 1 at À158C.
[15] Use of other tertiary amines such as iPr2EtN or NEt3 provided com-
parable results.
Received: April 17, 2009
Published online: August 20, 2009
Chem. Eur. J. 2009, 15, 10103 – 10109
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10109