Investigating sequence space: How important is the spatial arrangement of functional groups in the asymmetric aldol reaction catalyst H-Pro-Pro-Asp- NH2?

Article abstract of DOI:10.1002/adsc.200800053

H-Pro-Pro-Asp-NH₂ 1 is a versatile catalyst for asymmetric aldol reactions. Within the catalyst structure, both the N-terminal secondary amine and the carboxylic acid are crucial for efficient catalysis. Here, the importance of the arrangement of these two functional groups towards each other was examined. Several analogues of H-Pro-Pro-Asp-NH₂ were prepared in which the secondary amine and the carboxylic acid occupy different positions. Evaluation of their catalytic properties revealed that the placement of these two functional groups is highly critical for efficient catalysis. Even seemingly small structural modifications, for example, one methylene group more or less, can modify the catalytic properties significantly. The results demonstrate the difficulty in rationally designing a peptidic catalyst and the value of combinatorial smart screening methods for catalyst discovery.

Full text of DOI:10.1002/adsc.200800053

FULL PAPERS
DOI: 10.1002/adsc.200800053
Investigating Sequence Space: How Important is the Spatial
Arrangement of Functional Groups in the Asymmetric Aldol
Reaction Catalyst H-Pro-Pro-Asp-NH2?
a
a,
Jefferson D. Revell and Helma Wennemers *
a
Department of Chemistry, University of Basel, St. Johanns-Ring 19, 4056 Basel, Switzerland
Phone: (+41)-61-267-1146; fax: (+41)-61-267-0976
E-mail: Helma.Wennemers@unibas.ch
Received: January 24, 2008; Published online: April 11, 2008
Dedicated to Andreas Pfaltz.
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: H-Pro-Pro-Asp-NH 1 is a versatile cata- ties significantly. The results demonstrate the diffi-
2
lyst for asymmetric aldol reactions. Within the cata- culty in rationally designing a peptidic catalyst and
lyst structure, both the N-terminal secondary amine the value of combinatorial smart screening methods
and the carboxylic acid are crucial for efficient catal- for catalyst discovery.
ysis. Here, the importance of the arrangement of
these two functional groups towards each other was Abbreviations: Fmoc=9-fluorenylmethoxycarbonyl;
examined. Several analogues of H-Pro-Pro-Asp-NH2 HCTU=2-(6-chloro-1H-benzotriazole-1-yl)-1,1,3,3-
were prepared in which the secondary amine and the tetramethyluronium hexafluorophosphate; MSNT=
carboxylic acid occupy different positions. Evalua- 1-(mesitylene-2-sulfonyl)-3-nitro-1H-1,2,4-triazole;
tion of their catalytic properties revealed that the TNBS=2,4,6-trinitrobenzenesulfonic acid.
placement of these two functional groups is highly
critical for efficient catalysis. Even seemingly small
structural modifications, for example, one methylene Keywords: aldol reactions; asymmetric synthesis;
group more or less, can modify the catalytic proper- organocatalysis; peptides; proline
[
6]
Introduction
ric aldol reactions. This work also demonstrated that
the purely rational design of efficient peptidic cata-
Peptides are becoming increasingly popular as asym- lysts for aldol reactions is not trivial. The many de-
metric organocatalysts for a range of different reac- grees of freedom of even short-chain peptides renders
[1]
tions. Whilst consisting of the building blocks from prediction of their conformational and catalytic prop-
which nature constructs enzymes, their molecular erties challenging. Combinatorial chemistry has there-
weight is often comparable to that of typical synthetic fore served as an important tool within the develop-
[
1,7,8]
catalysts. With many peptidic catalysts, high yields ment process of many peptidic catalysts.
Using the
and selectivities are achieved under mild reaction method of “catalyst-substrate coimmobilization”
conditions. Another attractive feature is their modular which allows identification of catalysts within split-
[
9]
nature which allows for facile modification of struc- and-mix libraries, we discovered the peptides H-
tural and functional properties. Since the aldol reac- Pro-Pro-Asp-NH2 and H-Pro-d-Ala-d-Asp-NH as
2
[
10]
tion is one of the most important carbon-carbon bond catalysts for asymmetric aldol reactions. Both pep-
forming reactions, a significant amount of research tides emerged as consensus sequences from the
has been devoted to the development of efficient cat- screening of 3375 different tripeptides for catalytic ac-
[
2–5]
alysts for this transformation.
Inspired by type I al- tivity. Subsequent solution-phase experiments re-
dolases and/or secondary amine-based organocata- vealed that in particular H-Pro-Pro-Asp-NH 1, is a
2
[3–5]
lysts,
Reymond, List, Gong and others prepared highly active and selective catalyst: 1 mol% of 1 suffi-
peptides bearing N-terminal proline residues and ces to catalyze aldol reactions between acetone and
showed that peptidic catalysts can catalyze asymmet- several aldehydes with good to excellent yields and
1046
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Adv. Synth. Catal. 2008, 350, 1046 – 1052

Investigating Sequence Space: How Important is the Spatial Arrangement
FULL PAPERS
ing that subtle differences in the structure of peptidic
catalysts can have significant effects on their catalytic
properties.
Results and Discussion
Design of Analogues of the Asymmetric Catalyst
H-Pro-Pro-Asp-NH (1)
2
To evaluate the importance of the spatial arrange-
ment of the secondary amine and the carboxylic acid
within peptide 1, we examined the catalytic properties
of closely related peptides 2–7 and diastereoisomers
thereof (Scheme 2).
Peptides 2–7 differ from 1 in the spacer of the car-
boxylic acid and/or the C-terminal amide. In addition,
analogues without a C-terminal amide were investi-
gated. Specifically, H-Pro-Pro-Glu-NH 2 has an addi-
2
tional methylene group, whereas H-Pro-Pro-d-Asn-
OH 3 lacks a methylene group in the spacer to the
carboxylic acid. H-Pro-Pro-b-Asp-NH 4 has an addi-
2
tional methylene group in the spacer to the C-termi-
nal amide, whereas in its analogue H-Pro-Pro-b-Asp-
Scheme 1. a) Aldol reactions catalyzed by H-Pro-Pro-Asp-
NH 1 and b) lowest energy structure of 1 as predicted by
2
[10]
calculations using MacroModel 8.0.
enantioselectivities (Scheme 1a). In comparion, 30
mol% of proline is required to obtain the products in
comparable yields and enantioselectivities, demon-
strating that the higher complexity of the tripeptidic
catalyst is an excellent trade-off for higher activi-
[10,11]
ty.
Molecular modeling combined with CD-spectro-
scopic analysis suggest that peptide 1 preferentially
adopts a turn-conformation in which the secondary
amine and carboxylic acid are in close proximity to
[
10]
each other (Scheme 1b). Both the secondary amine
and the carboxylic acid are crucial for effective cataly-
sis by 1; replacement of either functional group leads
to a strong reduction or total loss of catalytic activity
[12]
and selectivity. This finding suggests that peptide 1
catalyzes asymmetric aldol reactions by a mechanism
[
4,13]
similar to that proposed for proline catalysis.
We
have now addressed the question how crucial the spa-
tial arrangement of these functional groups is for ef-
fective catalysis.
Within this work we present the catalytic properties
in aldol reactions of 17 closely related structural ana-
logues of peptide 1, bearing the secondary amine and
carboxylic acid functionalities in different positions.
Among these analogues, several were members of the
originally tested library, however, most were not. As
we will show, none of the analogues performed better Scheme 2. Peptides 2–7 closely related to the asymmetric
in aldol reactions compared to peptide 1, demonstrat- catalyst 1.
Adv. Synth. Catal. 2008, 350, 1046 – 1052
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
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Jefferson D. Revell and Helma Wennemers
FULL PAPERS
Table 1. Catalytic properties of peptides 2–7 in the aldol reaction between p-nitrobenzaldehyde and acetone.
[a]
[b]
Entry
Catalyst
Time [h]
Yield [%]
ee [%]
1
2
3
4
5
6
7
H-Pro-Pro-Asp-NH (1)
4
9
8
80
2
H-Pro-Pro-Glu-NH (2)
18
18
4
4
18
18
81
72
9
87
81
77
64
80
2
H-Pro-Pro-d-Asn-OH (3)
3
H-Pro-Pro-b -Asp-NH (4)
2
76
2
3
H-Pro-Pro-b -Asp-OH (5)
78
76
75
H-Pro-Pro-b-Ala-OH (6)
H-Pro-Pro-Gly-OH (7)
[
[
a]
b]
Isolated yields.
The ee was determined by chiral stationary HPLC analysis.
OH 5 this amide is replaced by a carboxylic acid. Pep- Catalytic Properties of Peptides 2–7 in Direct Aldol
tides H-Pro-Pro-b-Ala-OH 6 and H-Pro-Pro-Gly-OH Reactions
7
lack the C-terminal amide entirely.
To allow for a comparison of the catalytic properties
of the closely related peptides 2–7, the aldol reaction
between acetone and p-nitrobenzaldehyde was used
as a test reaction (Table 1).
Synthesis of Peptides 2–7
All peptides were prepared by solid phase peptide
All peptides proved catalytically active providing
synthesis using Wang resin for those bearing a C-ter- the aldol product in good to very good yields and
minal carboxylic acid and Rink amide resin to obtain enantioselectivities. A closer look, however, reveals
a C-terminal amide. The first two peptide couplings distinct differences in their catalytic properties: with
were performed with a-N-Fmoc protected amino peptide 2 bearing a glutamic acid in place of the as-
acids bearing acid sensitive groups on the side-chain partic acid residue, the aldol product is obtained in
functional groups (t-Bu for Asp and b-Asp, trityl for significantly lower enantiomeric purity compared to
Asn). For the N-terminal proline residue a-N-Boc- the parent peptide 1 (Table 1, entry 2). This suggests
Pro-OH was employed. Wang resin was functional- that side chains with a greater flexibility are detrimen-
ized using MSNT and N-methylimidazole as coupling tal to enantioselectivity in asymmetric aldol reactions.
reagent. Functionalization of the Rink-amide resin This is supported by the result obtained with peptide
was accomplished using HCTU/(i-Pr) NEt as coupling 3 bearing the carboxylic acid closer to the backbone
A
H
R
U
G
2
reagent, which was also used for all subsequent pep- of the peptidic catalyst. Peptide 3 is equally as enan-
tide couplings. A mixture of piperidine and DMF tioselective as peptide 1, only its reactivity is slightly
(
1:4) served for Fmoc deprotections. Removal of the compromised (Table 1, entry 3). Since the carbox-
peptides from the solid supports and deprotection of amide in 3 is by one methylene group further re-
AHCTREUNG
the carboxylic acid functional group in the side chain moved from the peptide backbone, peptide 4 which
was accomplished simultaneously with neat trifluoro- differs from 1 only in the position of the carboxamide
acetic acid (TFA). All peptides were prepared on a was prepared and tested. Peptide 4 as well as its car-
500-mg scale and were isolated and used as their TFA boxylic acid analogue 5 exhibited comparable reactiv-
salts without any further purification. ities and selectivities to peptide 1. This demonstrates
All amino acid derivatives were commercially avail- that the position of the carboxylic acid is key for high
3
able apart from the b-aspartic acid derivative. H-b - enantioselectivity and suggests that the carboxamide
Asp
A
C
H
T
R
E
U
N
G
(t-Bu)-OH was prepared starting from dimethyl plays a role in tuning the reactivity. These conclusions
3-oxoglutarate by a route previously reported by are supported by the results obtained with peptides 6
[14]
Crossley. Protection of the amino group was accom- and 7 both of which lack the carboxamide (Table 1,
plished under Schotten–Baumann conditions using entries 6 and 7). Their enantioselectivity is compara-
3
Fmoc-Cl to yield the protected derivative Fmoc-b - ble to that of peptide 1, however, longer reaction
Asp
A
C
H
T
R
E
U
N
G
(t-Bu)-OH 8 which was used directly in the solid times are required to obtain the aldol products in
phase synthesis.
comparable yields.
1048
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Adv. Synth. Catal. 2008, 350, 1046 – 1052

Investigating Sequence Space: How Important is the Spatial Arrangement
FULL PAPERS
Table 2. Catalytic properties of diastereomers of peptide 1 in the aldol reaction between p-nitrobenzaldehyde and acetone.
[
a]
[b]
Entry
Catalyst
Time [h]
Yield [%]
9
ee [%]
Absolute conf.
1
2
H-Pro-Pro-Asp-NH (1)
H-d-Pro-d-Pro-d-Asp-NH (ent-1)
H-Pro-Pro-d-Asp-NH (1a)
H-Pro-d-Pro-Asp-NH (1b)
4
4
18
18
18
8
S )8 0
R)
(S)
(S)
(R)
(
2
9
6
79
(
2
[
[
[
c]
c]
c]
3
4
5
46
53
58
33
31
45
2
2
H-d-Pro-Pro-Asp-NH (1c)
2
[
[
[
a]
Isolated yields, in entries 3–5 unreacted aldehyde could be reisolated, essentially no side products were observed.
The ee was determined by chiral stationary HPLC analysis.
Longer reaction times (e.g., 36 h) resulted in slightly increased product yields but identical enantiomeric excesses.
b]
c]
Catalytic Properties of Diastereoisomers of Peptides
–4 in Direct Aldol Reactions
lytic performances of the structurally similar peptides,
CD spectroscopic studies and conformational searches
using the program MacroModel 8.0 with the OPLS
1
[
17,18]
The conformations of peptides containing the diaste- force field were performed.
These studies suggest
reomeric motifs l-Pro-Xxx and d-Pro-Xxx are known that, as expected, many of the peptides preferentially
[
15]
to differ from each other. Thus, inversion of the ab- adopt turn conformations. However, neither the de-
solute configuration at one or two of the chiral cen- rived lowest energy conformations nor the CD spec-
ters within the structure of peptide 1 can be expected troscopic data could be unambiguously correlated
to result in significantly modified spatial orientations with the observed catalytic properties of the peptides,
between the secondary amine and the carboxylic acid. once again demonstrating the difficulty of rationally
To investigate the catalytic properties of stereoiso- designing a peptidic catalyst.
mers of peptide 1 all three possible diastereoisomers
were prepared and used to catalyze the test reaction
between p-nitrobenzaldehyde and acetone (Table 2). Conclusions
Also the enantiomer of 1, H-d-Pro-d-Pro-d-Asp-NH2
(
ent-1) was examined and as expected provided the We have shown that slight modifications in the struc-
enantiomeric aldol product in the same yield and ture of the peptidic catalyst H-Pro-Pro-Asp-NH (1)
2
enantioselectivity as observed for 1 (Table 2, entry 2). can have profound effects on the catalytic properties
All diastereoisomers of peptide 1 are poor asym- in asymmetric aldol reactions. None of the 17 exam-
metric catalysts for the examined aldol reaction pro- ined structural analogues of 1 exhibited superior cata-
viding the aldol products in low yields and enantiose- lytic properties compared to 1; either lower enantio-
lectivities. This result demonstrates the importance of selectivity or lower reactivity or both were observed.
the spatial arrangement of the functional groups The most dramatically altered catalytic properties
within peptide 1 with regard to asymmetric aldol reac- were observed with diastereoisomers of 1 but even
[16]
tions.
Interestingly, the diastereoisomer H-d-Pro- seemingly small structural changes like an additional
Pro-Asp-NH 1c provides the opposite enantiomer of methylene group were found to have significant ef-
2
the aldol product compared to the all-L configured fects. These results demonstrate the difficulty in ra-
parent peptide 1. This further demonstrates that slight tionally designing an asymmetric peptidic catalyst and
structural modifications within peptidic catalysts can highlight the value of smart combinatorial screening
lead to significantly altered stereoselectivities. With methods for catalyst discovery.
this in mind, we also examined the catalytic proper-
ties of diastereoisomers of peptides 2–4. Similarly to
peptides 1a–1c, these stereoisomers proved to be less
efficient catalysts in the examined aldol reaction com-
pared to their parent structures (Table 3).
These results further demonstrate the importance
of the spatial arrangement of the secondary amine
Experimental Section
General Aspects and Materials
Materials and reagents were of the highest commercially
and carboxylic acid for effective catalysis of aldol re- available grade and used without further purification. Reac-
actions. In an attempt to rationalize the different cata- tions were monitored by thin-layer chromatography using
Adv. Synth. Catal. 2008, 350, 1046 – 1052
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
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Jefferson D. Revell and Helma Wennemers
FULL PAPERS
Table 3. Catalytic properties of diastereomers of peptides 2–4 in the aldol reaction between p-nitrobenzaldehyde and ace-
tone.
[a]
[b]
Entry
Catalyst
Time [h]
Yield [%]
ee [%]
Absolute conf.
1
2
H-Pro-Pro-Glu-NH (2)
18
18
18
18
18
18
18
18
4
81
40
56
68
65
72
47
64
9
64
30
14
39
73
80
39
36
(S)
(S)
(S)
( R)
(S)
(S)
( S)
(R)
76 S)
(R)
2
H-Pro-Pro-d-Glu-NH (2a)
2
[
[
[
[
[
[
c]
c]
c]
c]
c]
c]
3
4
5
6
7
8
9
1
H-Pro-d-Pro-Glu-NH (2b)
2
H-d-Pro-Pro-Glu-NH (2c)
2
H-Pro-Pro-Asn-OH (3)
H-Pro-Pro-d-Asn-OH (3a)
H-Pro-d-Pro-Asn-OH (3b)
H-d-Pro-Pro-Asn-OH (3c)
3
H-Pro-Pro-
0
b -Asp-NH (4)
2
(
2
3
H-d-Pro-d-Pro-b -Asp-NH (4a)
4
73
65
2
[
[
[
a]
Iolated yields, in all reactions unreacted aldehyde could be reisolated, essentially no side products were observed.
The ee was determined by chiral stationary HPLC analysis.
Longer reaction times (e.g., 36 h) resulted in slightly increased product yields but identical enantiomeric excesses.
b]
c]
Merck silica gel 60 F254 plates. Compounds were visualized General Procedure for Fmoc Deprotections
under UV and with KMnO . Flash chromatography was per-
4
1
20% piperidine in DMF was added to the resin (pre-swollen
in DMF) and the reaction mixture was agitated for 5 min,
drained and the piperidine treatment repeated for 10 min.
formed using Merck silica gel 60, particle size 40–63 mm. H
13
and C NMR spectra were recorded on a Bruker DPX 400
spectrometer. Chemical shifts are reported in ppm using the
residual solvent peak as a reference. HPLC analyses were
performed on an analytical instrument with a diode array
detector from Shimadzu. Specific rotations were measured
on a Perkin–Elmer Polarimeter 341.
The resin was then washed with DMF and CH Cl2 (5”
2
each). Both couplings and deprotections were monitored by
[
19]
[20]
TNBS, 21q]ualitative Kaiser, and chloranil tests (secondary
[
amines).
General procedures for the syntheses of the various pepti-
dic catalyst types are given below.
General Procedure for Cleavage of Peptides from the
Solid Support
General Protocols for Solid-Phase Synthesis
Immobilized peptides were cleaved into solution through ag-
itation of the resin in neat TFA for 1 h, then repeating the
acid treatment for a further 30 min. Pooling of filtrates and
removal of volatiles under vacuum followed by precipitation
Peptides were prepared on solid-phase (either Rink amide
AM or Wang OH resin purchased from BACHEM) follow-
ing the general protocol for Fmoc/t-Bu peptide synthesis.
and thorough washing with Et O afforded the peptides as
2
their trifluoroacetate salts that were dried under high
General Procedure for Functionalization of Wang
Resin
vacuum
and
used
without
further
purification.
TFA·H-l-Pro-l-Pro-l-Asp-NH2 (1): Prepared according
To a pre-swollen suspension of Wang OH resin in CH Cl ,
1
2
2
to the general protocols for solid-phase synthesis. The H
was added a solution of the Fmoc amino acid (3 equiv.), N-
methylimidazole (2.5 equiv.) and MSNT (3 equiv.) in
CH Cl . The reaction mixture was agitated at room temper-
13
and C NMR spectra show a double set of peaks in a ratio
of 5:1 due to s-trans and s-cis conformers around the tertiary
amide. major conformer. H NMR (500 MHz, D O, 25 8C):
d=4.63 (dd, J=8.3 Hz, 6.3 Hz, 1H), 4.53 (dd, J=7.3 Hz,
1
2
2
2
ature for 1 h, then washed with DMF and CH Cl (5”
2
2
each). Quantitative Fmoc tests were performed as spot
checks.
5
3
5
1
.9Hz, 1H), 4.48 (dd, J=8.1 Hz, 6.1 Hz, 1H), 3.70 (m, 1H),
.60 (m, 1H), 3.44 (m, 1H), 3.39(m, 1H), 2.68 (dd, J=
.8 Hz, 3.9Hz, 1H), 2.57 (m, 1H), 2.35 (m, 1H), 2.31 (m,
1
3
H), 2.11–1.91 (m, 6H); C NMR (125.8 MHz, D O, 25 8C):
2
General Procedure for Peptide Couplings
d=177.0, 175.7, 173.4, 168.3, 60.6, 59.1, 51.1, 47.7, 46.5, 38.0,
29.2, 28.3, 24.5, 23.8; minor conformer: H NMR (500 MHz,
1
i-PrNEt (9equiv. as a 3M solution in N-methylpyrrolidone)
2
was added to a solution of Fmoc-Xxx-OH (3 equiv.) and
HCTU (3 equiv.) in DMF. The activated amino acid was
added to the amino-functionalized resin swollen in DMF
D O, 25 8C): d=4.67 (dd, J=10.1 Hz, 4.2 Hz, 1H), 4.56 (dd,
2
J=8.5 Hz, 2.8 Hz, 1H), 4.16 (dd, J=8.5 Hz, 7.4 Hz, 1H),
3.65 (m, 1H), 3.53 (m, 1H), 3.44 (m, 1H), 3.39(m, 1H),
2.74, (dd, J=15.8 Hz, 4.3 Hz, 1H), 2.48 (m, 1H), 2.41 (m,
1H), 2.18 (m, 1H), 2.01 (m, 1H), 2.11–1.91 (m, 5H);
(
1
~100 mM concentration) and the mixture was agitated for
.5 h before washing with DMF and CH Cl (5” each).
2
2
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Adv. Synth. Catal. 2008, 350, 1046 – 1052

Investigating Sequence Space: How Important is the Spatial Arrangement
FULL PAPERS
1
3
C NMR (125.8 MHz, D O, 25 8C): d=177.1, 175.5, 173.0, References
2
1
3
68.3, 59.8, 58.9, 51.5, 47.9, 46.6, 38.7, 31.7, 28.5, 23.9, 21.9;
HR-MS (ESI): m/z=327.1661, calcd. for C H N O :
[1] For reviews see a) E. A. Colby Davie, S. M. Mennen,
Y. Xu, S. J. Miller, Chem. Rev. 2007, 107, 5759; b) J. D.
Revell, H. Wennemers, Curr. Opin. Chem. Biol. 2007,
11, 269; c) A. Berkessel, Curr. Opin. Chem. Biol. 2003,
7, 409; d) M. H. Fonseca, B. List, Curr. Opin. Chem.
Biol. 2004, 8, 319; e) S. J. Miller, Acc. Chem. Res. 2004,
37, 601, and references cited therein.
1
4
23
4
5
27.1668.
TFA·H-l-Pro-l-Pro-d-Asp-NH (1a): Prepared according
2
1
to the general protocols for solid-phase synthesis. H NMR
(
(
400 MHz, D O, 25 8C): d=4.77 (m, 1H), 4.64 (m, 1H), 4.51
dd, J=5.9Hz, 8.5 Hz, 1H), 3.71 (m, 1H), 3.62 (m, 1H),
.42 (m, 2H), 2.89(dd, J=5.1 Hz, 15.8 Hz, 1H), 2.80 (dd,
2
3
J=7.6 Hz, 15.7 Hz, 1H), 2.62 (m, 1H), 2.32 (m, 1H), 2.12–
[2] Modern Aldol Reactions, (Ed.: R. Mahrwald), Wiley
VCH, Weinheim, 2004, Vols. 1 and 2.
13
1
1
2
.89(m, 6H);
C NMR (100 MHz, D O, 25 8C): d=175.3,
2
74.6, 173.9, 168.8, 61.2, 59.8, 50.1, 48.4, 47.3, 37.1, 30.2, 29.1,
5.2, 24.6; HR-MS (ESI): m/z=327.1668, calcd. for
[3] For recent reviews on secondary amine based organo-
catalysts used in aldol and related reactions, see: a) S.
Mukherjee, J. W. Yang, S. Hoffmann, B. List, Chem.
Rev. 2007, 107, 5471; b) A. Erkkilä, I. Majander, P. M.
Pihko, Chem. Rev. 2007, 107, 5416; c) G. Guillena, C.
Nàjera, D. J. Ramón, Tetrahedron: Asymmetry 2007, 18,
C H N O : 327.1668.
1
4
23
4
5
TFA·H-l-Pro-d-Pro-l-Asp-NH (1b): Prepared according
2
1
to the general protocols for solid-phase synthesis. H NMR
(
400 MHz, D O, 25 8C): d=4.75 (dd, J=4.8 Hz, 8.4 Hz, 1H),
2
4
6
2
1
6
1
2
3
.63 (m, 1H), 4.45 (dd, J=4.9Hz, 8.7 Hz, 1H), 3.73 (td, J=
.5 Hz, 10.1 Hz, 1H), 3.62 (td, J=7.0, 10.0, 1H), 3.42 (m,
H), 2.97 (dd, J=4.8 Hz, 17.0 Hz, 1H), 2.85 (dd, J=8.4 Hz,
7.0 Hz, 1H), 2.56 (m, 1H), 2.30 (m, 1H), 2.12–1.93 (m,
2
249; d) B. List, Chem. Commun. 2006, 819; e) C. F.
Barbas III, Angew. Chem. Int. Ed. 2008, 47, 42.
4] For early examples see: a) B. List, R. A. Lerner, C. F.
Barbas III, J. Am. Chem. Soc. 2000, 122, 2395; b) K.
Sakthivel, W. Notz, T. Bui, C. F. Barbas III, J. Am.
Chem. Soc. 2001, 123, 5260; c) S. Saito, M. Nakadai, H.
Yamamoto, Synlett 2001, 1245.
5] For further examples of direct aldol reactions catalyzed
by proline and modified proline-based catalysts see:
a) Z. Tang, F. Jiang, L.-T. Yu, X. Cui, L.-Z. Gong, A.-
Q. Mi, Y.-Z. Jiang, Y.-D. Wu, J. Am. Chem. Soc. 2003,
[
13
H); C NMR (100 MHz, D O, 25 8C): d=175.4, 174.6,
2
74.6, 168.5, 61.5, 59.7, 50.3, 48.2, 47.1, 35.9, 29.8, 28.6, 24.9,
4.4; HR-MS (ESI): m/z=327.1668, calcd. for C H N O :
1
4
23
4
5
27.1668.
TFA·H-d-Pro-l-Pro-l-Asp-NH (1c): Prepared according
[
2
1
to the general protocols for solid-phase synthesis. H NMR
(
400 MHz, D O, 25 8C): d=4.71 (dd, J=5.3 Hz, 8.4 Hz, 1H),
2
4.64 (dd, J=7.1 Hz, 8.7 Hz, 1H), 4.46 (dd, J=3.7 Hz, 8.6 Hz,
1H), 3.73 (m, 1H), 3.60 (m, 1H), 3.42 (m, 2H), 2.97 (dd, J=
5.3 Hz, 16.9Hz, 1H), 2.84 (dd, J=8.4 Hz, 16.8 Hz, 1H), 2.55
1
25, 5262; b) A. J. A. Cobb, D. M. Shaw, S. V. Ley, Syn-
lett 2004, 558; c) H. Torii, M. Nakadai, K. Ishihara, S.
Saito, H. Yamamoto, Angew. Chem. 2004, 116, 2017;
Angew. Chem. Int. Ed. 2004, 43, 1983; d) A. Hartikka,
P. I. Arvidsson, Tetrahedron: Asymmetry 2004, 15, 1831;
e) N. Mase, F. Tanaka, C. F. Barbas III, Angew. Chem.
1
3
(
(
m, 1H), 2.31 (m, 1H), 2.11–1.97 (m, 6H); C NMR
100 MHz, D O, 25 8C): d=175.2, 174.5, 174.3, 168.9, 61.4,
2
58.8, 50.4, 48.1, 47.1, 35.8, 29.9, 28.5, 24.7, 24.4; HR-MS
(
ESI): m/z=327.1661, calcd. for C H N O : 327.1668.
1
4
23
4
5
2
004, 116, 2474; Angew. Chem. Int. Ed. 2004, 43, 2420;
f) E. Lacoste, Y. Landais, K. Schenk, J.-B. Verlhac, J.-
M. Vincent, Tetrahedron Lett. 2004, 45, 8035; g) A. Ber-
kessel, B. Koch, J. Lex, Adv. Synth. Catal. 2004, 346,
General Procedure for Aldol Reactions
The peptide (0.004 mmol, 1 mol%) was suspended in a stan-
dard solution of N-methylmorpholine (0.5 mL, 0.004 mmol)
and 4-nitrobenzaldehyde (60 mg, 0.40 mmol) in acetone
1
141; h) A. J. A. Cobb, D. M. Shaw, D. A. Longbottom,
J. B. Gold, S. V. Ley, Org. Biomol. Chem. 2005, 3, 84;
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(
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2
3
407; j) D. Gryko, R. Lipinski, Adv. Synth. Catal. 2005,
47, 1948; k) Z. Tang, Z.-H. Tang, X.-H. Chen, L.-F.
temperature for the indicated period, then applied directly
to silica gel (15 g), eluting with 40% EtOAc in pentanes to
afford the aldol product. Enantiomeric excess was deter-
Cun, A.-Q. Mi, A.-Q. Mi, Y.-Z. Jiang, L.-Z. Gong, J.
Am. Chem. Soc. 2005, 127, 9285; l) S. Samanta, J. Liu,
R. Dodda, C.-G. Zhao, Org. Lett. 2005, 7, 5321; m) W.
Wang, H. Li, J. Wang, Tetrahedron Lett. 2005, 46, 5077;
n) T. Kano, J. Takai, O. Tokuda, K. Maruoka, Angew.
Chem. 2005, 117, 3115; Angew. Chem. Int. Ed. 2005, 44,
À1
mined by chiral HPLC (AS-column), 0.5 mLmin , 1:1
A
C
H
T
R
E
U
N
G
hexanes:i-PrOH, 20 mins run, 408C. For full characteriza-
[4,10]
tion of the aldol product see refs.
3
055; o) T. Kano, O. Tokuda, K. Maruoka, Tetrahedron
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This work was supported by BACHEM and the Swiss Na-
tional Science Foundation. We thank the EU for support by
the Research Training Network REVCAT and Prof. J.-L.
Reymond (University of Bern) for recording the HR-mass
spectra. H.W. is grateful to BACHEM for an endowed profes-
sorship.
8
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ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 1046 – 1052