N-primary-amine-terminal β-turn tetrapeptides as organocatalysts for highly enantioselective aldol reaction

Article abstract of DOI:10.1021/jo9005766

(Chemical Equation Presented) Tetrapeptides, containing a terminated primary amine and conformationally restricted D-Pro-Gly or D-Pro-Aib (2-aminoisobutanoic acid) segment as a strongly β-turn-nucleating element, were designed and synthesized with condens

Full text of DOI:10.1021/jo9005766

N-Primary-Amine-Terminal ꢀ-Turn Tetrapeptides as
Organocatalysts for Highly Enantioselective Aldol Reaction
Feng-Chun Wu,† Chao-Shan Da,*,†,‡ Zhi-Xue Du,† Qi-Peng Guo,† Wei-Ping Li,§ Lei Yi,†
Ya-Ning Jia,† and Xiao Ma†
Institute of Biochemistry & Molecular Biology, School of Life Sciences, State Key Laboratory of Applied
Organic Chemistry, Lanzhou UniVersity, Lanzhou 730000, China, and Department of Biology, Shantou
UniVersity, Shantou 515063, China
dachaoshan@lzu.edu.cn
ReceiVed March 16, 2009
Tetrapeptides, containing a terminated primary amine and conformationally restricted D-Pro-Gly or D-Pro-
Aib (2-aminoisobutanoic acid) segment as a strongly ꢀ-turn-nucleating element, were designed and
synthesized with condensation of N-module dipeptides with C-module dipeptides in solution. They were
first applied to catalyze aldol reactions, and were found to be effective catalysts for the transformations.
The tetrapeptide Val-D-Pro-Gly-Leu-OH (1g) was the optimal organocatalyst. It was shown that the
intensive ꢀ-turn conformation, indicated by CD and NOESY spectra, contributed to the (R)-aldol and
high enantioselectivity of the reaction of acetone in MeOH, whereas the sharply varied conformation
should contribute to the low enantioselectivity and (S)-product of the reaction in 1,2-dichloroethane (DCE).
The asymmetric induction in the reaction of hydroxyacetone was not affected by solvents, and predominant
anti products were achieved by 1g in MeCN with the additive (S)-BINOL.
Introduction
molecules as efficient chiral organocatalysts in this reaction are
currently very interesting for chemists and have shown fruitful
results.3
The asymmetric aldol reaction, which forms C-C bonds and
generates chiral carbons, is a key reaction in organic synthesis,
with remarkable biological and prebiological significance,1 and
thus has been at the center of research.2 And simple small
There has recently been an increase in the application of
peptides as catalysts for asymmetric reactions.4 Benefiting
greatly from advances in the understanding of enzyme-mediated
biosynthesis, biomimetic synthesis has been a new field of
extensive research.3a,5 Synthetic peptides as interesting and
important artificial enzymes are attractive because structural
modifications can easily be introduced and used for fine-tuning
of the catalytic properties. Unlike structurally simple and small
molecular organocatalysts, higher structural artificial peptidic
enzymes are more structurally similar to enzymes. The suc-
cessful application experiences of synthetic peptidic catalysts
in organic reactions will return to greatly contribute to the
† Institute of Biochemistry & Molecular Biology, School of Life Sciences.
‡ State Key Laboratory of Applied Organic Chemistry.
§ Shantou University.
(1) (a) Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH: Weinheim,
Germany, 2004; Vols. 1 and 2. (b) Casiraghi, G.; Zanardi, F.; Appendino, G.;
Rassu, G. Chem. ReV. 2000, 100, 1929.
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7398. (b) Kantam, M. L.; Ramani, T.; Chakrapani, L.; Kumar, K. V. Tetrahedron
Lett. 2008, 49, 1498. (c) Paradowska, J.; Stodulski, M.; Mlynarski, J. AdV. Synth.
Catal. 2007, 349, 1041. (d) Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000, 122,
12003. (e) Trost, B. M.; Silcoff, E. R.; Ito, H. Org. Lett. 2001, 3, 2497. (f) Kumagai,
N.; Matsunaga, S.; Yoshikawa, N.; Ohshima, T.; Shibasaki, M. Org. Lett. 2001, 3,
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Da, C.-S. Tetrahedron Lett. 2009, 50, 3059.
(3) For recent reviews on organocatalytic aldol reactions, see: (a) Gro¨ger,
H.; Wilken, J. Angew. Chem., Int. Ed. 2001, 40, 529. (b) Guillena, G.; Na´jera,
C.; Ramo´n, D. J. Tetrahedron: Asymmetry 2007, 18, 2249. (c) Carrea, G.;
Ottolina, G.; Lazcano, A.; Pirontic, V.; Colonna, S. Tetrahedron: Asymmety 2007,
18, 1265.
4812 J. Org. Chem. 2009, 74, 4812–4818
10.1021/jo9005766 CCC: $40.75  2009 American Chemical Society
Published on Web 05/21/2009

N-Primary-Amine-Terminal ꢀ-Turn Tetrapeptides
development of research on enzyme-mediated synthesis. Now,
researchers have concentrated on two classes of peptides in the
asymmetric aldol reaction. One type is the peptide of N-terminal
proline. The application of N-prolyl peptides has indeed proven
to be a fertile ground for the development of the peptide-
catalyzed asymmetric reaction.6 Another type is the peptide of
N-terminal primary amino acids, which is more interesting
because N-terminal primary amine is the catalytic function group
in the active center of natural aldolases.2h-j In the earlier works,
however, the enantioselective results of the asymmetric aldol
reactions catalyzed by peptides bearing primary amines were
far inferior to the N-prolyl peptides, especially the reaction of
acetone with aldehydes.4c,7 This result might be attributed to
the less successful enantioselective outcomes of primary amine
organocatalysts in the asymmetric aldol reaction than that of
secondary amine organocatalysts. Recently, the research of
primary amine organocatalysts has been improved remarkably.8
It would greatly contribute to the highly efficient primary amine
peptides in the reaction. The former successful primary amine
peptides were mainly applied to the aldol reaction of cycloke-
tones and the aldol dimerization of glycoaldehyde to D-erythrose
or D-threose,9 nevertheless, they had unattractive behavior in
reactions of methyl alkyl ketones.7,10
Just as enzymes, some functional groups, which are far away
from each other in the primary structure, are close enough to
each other in the rigid space to form the active center and work
synergistically. However, only a few reports have been disclosed
that the higher structure of peptides, which are certainly essential
topics for the artificial polypeptidic enzyme mimics,11 could
contribute to high activity and enantioselectivity in this reaction.
Colonna and co-workers disclosed that PLL (polyleucine) with
secondary R-helix structure,12 which have been an excellent
catalyst for the asymmetric Julia´-Colonna epoxidation reaction
of electron-deficient ketenes,13 was an effective catalyst for the
aldol reaction of cyclohexanone with less than 76% ee as well.
The ꢀ-turn, a fundamental element of the ꢀ-hairpin, is a common
feature within proteins and enzymes, encompassing on average
25% of the residues.14 And some synthetic ꢀ-turn peptides as
effective chiral catalysts have been successfully reported in
several asymmetric catalytic reactions.15 However, there are only
two disclosed successful examples in the asymmetric aldol
reaction catalyzed by ꢀ-turn peptides to date. Wennemers’ group
suggested that a turn-like conformation of a N-prolyl tripeptide
was important for orienting the two functional groups into close
vicinity, which was crucial for efficient catalysis of acetone with
up to 91% ee.6b And it was then rechecked by Reiser and co-
workers, using aminocyclopropane carboxylic acids to stabilize
the secondary structure of their N- and C-prolyl R/ꢀ-tripeptide.16
Thus, research on high-efficiency and higher-structure peptidic
organocatalysts is greatly challenging and eagerly desired on
account of biomimetic catalysis in this reaction. It is clear that
there is no ꢀ-turn tetrapeptides with a N-terminal primary amine
group, which is also one of the key function groups in the active
center of natural aldolases, as organocatalysts have been
disclosed in this reaction to date. Hererin we report our reults
on this topic.
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J. Org. Chem. Vol. 74, No. 13, 2009 4813

Wu et al.
Then we experimented on a series of additives with a gradient
pKa to increase the enantioselectivity. Interestingly, it seemed
that the pKa of additives greatly influenced the enantioselectivity.
Apparently, the acidic additives with pKa between 3.0 and 5.0,
except for DNP (2,4-dinitrophenol), bahaved better than others
in the enantioselectivity. PhCOOH (pKa 4.19) could mostly
improve the enantioselectivity from 66% up to 83% ee (entry
22). Too strong acidic additives such as trifluoroacetic acid
(TFA) gave no product at all (entry 27).
Then the enantioselective catalytic activities of the catalysts
1a-h were investigated. The results demonstrated that the
tetrapeptides with stable ꢀ-turn structure produced higher
enantioselectivities than di- and tripeptides. The dipeptide 1a
and tripeptide 1b nearly gave the same enantioselectivity as each
other. This result indicated that linkage of a further achiral Gly
to C-terminus of the dipeptide 1a did not contribute to the higher
enantioselecitivty. In current amino acid sequences, peptides
with a central D-Pro-Gly segment revealed better enantioselec-
tivities than that of peptide 1c with a central D-Pro-Aib segment
(entries 22 and 28-34). The tetrapeptide 1g turned out to be
the most effective. Application of the tetrapeptide 1i, the methyl
ester of 1g, afforded the sharply decreased enantioselectivity
and declined reactivity (entry 35). It indicated that the free
C-terminal carboxyl acid of the peptide played a crucial role in
the enantioselectivity and reactivity. Further optimizing experi-
ments showed that increasing the amount of catalyst to 20
mol % could improve its enantioselectivity up to 91% (entry
36). While increasing the additive loading to 40 mol %, excellent
enantioselectivity (95%) was harvested (entry 37). Notably, this
value is the highest ee in the reaction of acetone with
p-nitrobenzaldehyde catalyzed by N-primary-amine-terminal
peptidic catalysts to date.
FIGURE 1. Peptidic organocatalysts.
Results and Discussion
The dipeptides D-Pro-Gly and D-Pro-Aib have been proved
to greatly nucleate tight ꢀ-turn or ꢀ-hairpin secondary structures
even in short peptides.17 Therefore, as well as the di- and
tripeptides (Figure 1, 1a and 1b) for comparison purposes, a
series of tetrapeptide catalysts (Figure 1, 1c-i) bearing N-
terminal primary amines with these central segments were
designed.
The peptides 1b-g were synthesized by condensation of two
dipeptidic modules via a routine mixed anhydride procedure
(Scheme 1).18 The dipeptides 4a-c with N-terminal bulky amino
acids, such as valine, were synthesized with the DIC-HOBt
(DIC: diisopropylcarbodiimide; HOBt: N-hydroxybenzotriazole)
condensation method,19 whereas the dipeptides 4d-e without
N-terminal bulky amino acids were prepared by using the mixed
anhydride procedure. The N-terminal modules 5a,b and C-
terminal modules 5c-e were achieved from 4a,b and 4c-e after
partial deprotection of Boc and Bn with TFA and catalytic
hydrogenation, respectively. These modules were directly
condensed with each other without further purification, using
the mixed anhydride procedure, to give the protected peptides.
Removal of the whole protective groups from 4a and 6a-g, or
the Boc group from 6h, afforded the peptidic organocatalysts
1a-i.
Initially, 10 mol % of 1g was tested in the model reaction of
4-nitrobenzaldehyde with acetone at room temperature (Table
1). Screening a variety of solvents indicated that methanol was
optimal, with ee up to 66% (entry 2). Particularly noteworthy
was that the peptide catalyst generated aldol products with
opposite configurations despite the fact that there was no
difference but for the polarity of solvents. The configuration of
the product would be R when the reaction was carried out in
strongly polar solvents (entries 1-8), whereas it would be S in
both weakly polar and apolar solvents (entries 9-16). And
among apolar solvents, DCE (1,2-dichloroethane) gave the
highest ee with 40% (entry 14). It was speculated that the
different solvents, because of the hydrogen competition, might
have different impact on the secondary structure of the peptide,
and then change its catalytic activity and inductive direction.
The optimal protocol was expanded to aldol reactions of
acetone with a variety of aromatic aldehydes (Table 2).
Generally, the electron-withdrawing group on the aldehyde
facilitated the reaction proceeding to completion. High enanti-
oselectivities (up to 96% ee) but moderate yields were obtained
with electron-deficient aldehydes. It appeared that para-
substituted aromatic aldehydes, such as 4-nitrobenzaldehyde,
4-(trifluoromethyl)benzaldehyde, and 2,4-dichlorobenzaldehyde,
could give good yields and high enantioselectivities (entries 1,
4, and 7). When 1-naphthaldehyde and 2-naphthaldehyde were
used as electron acceptors, excellent enantioselectivities but poor
conversions to the aldol product were observed (entries 8 and
9). Actually, the severe dehydration made the reaction unable
to give high yields, especially for electron-donating aryl
aldehydes. And alkylaldehydes failed to give aldol products.
The reaction between methyl isobutyl ketone and p-nitroben-
zaldehyde also gained a high enantioselectivity (93% ee, entry
10), but a poor yield due to low activity. The peptide (1g) was
subsequently tested in the aldol reactions of representative cyclic
ketones (Table 2, entries 11-13). The reactions were observed
to give high yields (up to 87%) and enantioselectivities (up to
86% ee) but poor diastereoselectivities.
(17) (a) Venkatraman, J.; Shankaramma, S. C.; Balaram, P. Chem. ReV. 2001,
101, 3131. (b) Haque, T. S.; Little, J. C.; Gellman, S. H. J. Am. Chem. Soc.
1996, 118, 6975. (c) Jarvo, E. R.; Copeland, G. T.; Papaioannou, N.; Bonitatebus,
P. J., Jr.; Miller, S. J. J. Am. Chem. Soc. 1999, 121, 11638. (d) Syud, F. A.;
Stanger, H. E.; Mortell, H. S.; Espinosa, J. F.; Fisk, J. D.; Fry, C. G.; Gellman,
S. H. J. Mol. Biol. 2003, 326, 553. (e) Karle, I. L.; Awasthi, S. K.; Balaram, P.
Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 8189.
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Soc. 1966, 88, 1338. (b) Anderson, G. W.; Zimmerman, J. E.; Callahan, F. M.
J. Am. Chem. Soc. 1967, 89, 5012.
(19) (a) Ko¨nig, W.; Geiger, R. Chem. Ber. 1970, 103, 788. (b) Ko¨nig, W.;
Geiger, R. Chem. Ber. 1970, 103, 2024. (c) Kemp, D. S.; Wang, S. W.; Rebck,
J., Jr.; Mollan, R. C.; Banquer, C.; Subramanyam, G. Tetrahedron 1974, 30,
3955.
It was interesting that no effects of solvents on the config-
uration of aldol product could be observed likewise when
replacing acetone with hydroxyacetone, and each solvent gave
predominantly (S,S)-aldol (Table 3). Therefore, the similar great
influence of the peptide secondary structure on this reaction
could not surprisingly be investigated as the former reaction of
acetone. Apparently, the hydroxy group of the ketone abstracted
the different impact of these solvents on the configuration and
4814 J. Org. Chem. Vol. 74, No. 13, 2009

N-Primary-Amine-Terminal ꢀ-Turn Tetrapeptides
SCHEME 1. Synthesis of Peptidic Organocatalysts 1a-h
strongly made the tetrapeptide 1g only achieve the (S)-hydroxy
product. But the distinct effect on their enantioselectivities could
be observed, and MeCN was the optimal one. The results of
additives indicated that (S)-BINOL was the best selection (entry
11). Decrease on both enantioselectivity and diastereoselectivity
in the absence of the additive denoted the crucial role of (S)-
BINOL in this reaction (entry 12). Without tetrapeptide 1g,
however, only (S)-BINOL itself did not push the reaction in its
process at all (entry 13). Furthermore, it was notable that the
configuration of the additive BINOL could not impact the
asymmetric outcome of the reaction, whether (S)- or (R)-BINOL
as an additive afforded the same configuration of aldol product
in nearly identical enantioselectivities (entries 11 and 14), just
as Shan and co-worker had found in their research.20 This
observation indicated that BINOL functioned as an effective
cocatalyst to assist the tetrapeptide catalyst 1g to enhance the
activity and enantioselectivity of the asymmetric transformation.
An interesting phenomenon was that the predominant syn
products were achieved when PhCOOH was used as an additive
whereas anti products were principally obtained when other
additives were introduced in the reaction. Further improvements
of enantioselectivity and diastereoselectivity were achieved
under a lowered temperature at the cost of decreased reactivity
(entries 15-17). To our delight, the catalyst 1g was very active
in this reaction. The reaction between hydroxyacetone and
p-nitrobenzaldehyde was accomplished in 1.5 h at room
temperature (entry 11). Even at -10 °C, 30 h were enough to
complete the reaction (entry 16).
that anti-1,2-diols with high enantioselectivities (up to 91% ee,
entry 5) were obtained in the reactions, while syn-1,2-diols were
very easy to generate in most cases.21 And this is the first
successful case of branched isomeric products of hydroxyacetone
catalyzed by peptidic organocatalysts.6c Different from reactions
of acetone, it seemed that reactions of hydroxyacetone and ortho-
substituted aromatic aldehydes could give higher enantioselec-
tivities, such as 2-nitrobenzaldehyde and 2-trifluoromethylben-
zaldehyde (entries 5 and 7).
It is more interesting that the same peptidic catalyst generated
different enantioselectivity and configuration in the identical
reaction of acetone with 4-NO2PhCHO in different solvents,
such as methanol and DCE, although the nucleated D-Pro-Gly
segment strongly induced the type II ꢀ-turn structure. And the
remarkable catalytic properties of peptide 1g in methanol
suggested the existence of privileged conformations in which
the C- and N-termini should be close to each other. The end-
capped tetrapeptide Ac-Val-D-Pro-Gly-Leu-NMe2 has been
reported to fold largely into the ꢀ-hairpin comformation.17b To
address the question whether peptide 1g also created the ꢀ-turn
structure, CD (circular dichroism) and NOESY spectra of
tetrapeptide 1g were made.
It can be observed from the CD spectra (see Figure S1 in the
Supporting Information) that tetrapeptide 1g in methanol and
ethanol have very similar performance. This clearly indicates a
strong negative band at <195 nm, a highly intensive positive
band at 200 nm, and a weak band at 210 nm, suggesting the
presence of the ꢀ-turn structure of the peptide in alcohols.22
Compared with strongly polar organic solvents, however, the
CD curve flattens in water. The spectrum of 1g in DCE shows
So a variety of aromatic aldehydes with hydroxyacetone were
examined in the presence of 20 mol % of 1g in CH3CN and 20
mol % of (S)-BINOL as an additive (Table 4). It is noteworthy
(21) (a) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386. (b) Notz,
W.; Tanaka, F.; Barbas, C. F., III Acc. Chem. Res. 2004, 37, 580. (c) Alcaide,
B.; Almendros, P. Eur. J. Org. Chem. 2002, 1595.
(20) Zhou, Y.; Shan, Z. J. Org. Chem. 2006, 71, 9510.
J. Org. Chem. Vol. 74, No. 13, 2009 4815

Wu et al.
TABLE 1. Screening of Catalysts and Optimization of Conditions
TABLE 2. Reaction of Acetone and Cyclic Ketones with
Aldehydesa
entry
peptidea
solvent
H2O
MeOH
EtOH
i-PrOH
MeOH/THF
DMF
DMSO
DMSO/H2O
acetone
CH3CN
toluene
THF
additive (pKa)b
ee (%)c
entry
R1
R2,R3
H,H
H,H
H,H
H,H
H,H
H,H
time (h) yield (%)b
drc
ee (%)d
1
2
3
1g
1g
1g
1g
1g
1g
1g
1g
1g
1g
1g
1g
1g
1g
1g
1g
1g
1g
1g
1g
1g
1g
1g
1g
1g
1g
1g
1a
1b
1c
1d
1e
1f
13 (R)
66 (R)
20 (R)
17 (R)
46 (R)
0
15 (R)
18 (R)
25 (S)
25 (S)
31 (S)
5 (S)
28 (S)
40 (S)
13 (S)
6 (S)
20 (R)
32 (R)
54 (R)
55 (R)
60 (R)
83 (R)
50 (R)
74 (R)
45 (R)
10 (R)
1
2
3
4
5
6
7
8
9
4-NO2
3-NO2
2-NO2
4-CF3
2-CF3
2-Cl
2,4-di-Cl H,H
1-Naph
2-Naph
78
70
66
72
120
94
58
29
55
44
20
30
47
12
10
24
87
60
84
95
87
61
93
81
85
91
94
96
93
4
5d
6
7
8e
72
9
H,H
144
144
240
76
72
36
10
11
12
13
14f
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36g
37h
H,H
10e 4-NO2
11
12
13
H,i-Bu
4-NO2
2-NO2
4-NO2
-(CH2)3-
-(CH2)3-
-(CH2)2-
36/64 86(51)f
53/47 37(81)f
2/1
CH2Cl2
DCE
Et2O
73(81)f
a Entries 1-9, MeOH/acetone 3:2 (v/v); entry 10, MeOH/methyl
isobutyl ketone, 3:2 (v/v); entries 11 and 12, MeOH/cyclohexanone, 3/2
(v/v); entry 13, MeOH/cyclopentanone, 3/2 (v/v). b Isolated yields.
c Determined (anti/syn) by chiral HPLC. d Determined by chiral HPLC.
e Linear isomer determined by 1H NMR. f Ee of anti isomer; ee in
parentheses is of the syn isomer.
n-hexane
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
Et3N
DIPEA
NMM
PNP (7.15)
AcOH (4.75)
PhCOOH (4.19)
DNP (3.96)
HCOOH (3.75)
salicylic acid (2.98)
ClCH2COOH (2.82)
TFA (0.23)
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
TABLE 3. Optimization of Aldol Reaction of Hydroxyacetonea
30 (R)
31 (R)
13 (R)
47 (R)
60 (R)
58 (R)
73 (R)
19 (R)
91 (R)
95 (R)
entry solventb
additive (mol %)
time (h) anti/sync ee (%)d
1
2
3
4
5
6
7
8
MeOH
DMF
THF
PhCOOH (40)
PhCOOH (40)
PhCOOH (40)
7
2
2
2
1.5
1
1.5
1
40/60
42/58
41/59
47/53
42/58
56/44
56/44
61/39
62/38
58/42
63/37
43/57
42
32
38
38
51
75
73
76
78
76
81
49
PhCOOH
PhCOOH
PhCOOH
PhCOOH
1h
1i
1g
1g
CH2Cl2 PhCOOH (40)
CH3CN PhCOOH (40)
CH3CN 4-NO2PhCO2H (20)
CH3CN 2-NO2PhCO2H (20)
CH3CN 4-NO2Phenol (20)
CH3CN 3-NO2Phenol (20)
CH3CN 2-naphthnol (20)
CH3CN (S)-BINOL (20)
CH3CN
CH3CN (S)-BINOL (20)
CH3CN (R)-BINOL (20)
CH3CN (S)-BINOL (20)
CH3CN (S)-BINOL (20)
CH3CN (S)-BINOL (40)
PhCOOH
a 10 mol % of peptide was used unless noted otherwise. b 10 mol %
of additive was used. PNP ) p-nitrophenol. c Determined by chiral
HPLC. d MeOH/THF 1:1 (v/v). e DMSO/H2O 100/1 (v/v). f DCE )
1,2-dichloroethane. g 20 mol % of catalyst and 20 mol % of additive
were used. h 20 mol % of catalyst and 40 mol % of additive were used.
9
2
10
11
12
13e
14
15f
16g
17g
1.5
1.5
2
24
1.5
14
67/33
66/34
74/26
73/27
79
80
87
85
an obvious red-shifted and higher positive absorbance curve
from 215 to 225 nm in comparison with similar spectra in
methanol and ethanol. Thus, it could be conceivable that higher
conformations or secondary structures of this series peptidic
catalysts should be intensively solvent dependent. The intensive
secondary ꢀ-turn structure of 1g formed in methanol would
contribute to high enantioselectivity and (R)-configuration,
whereas the greatly varied secondary structure of 1g in DCE
should contribute to the low enantioselectivity and (S)-config-
uration. Moreover, it can be clearly observed that addition of
benzoic acid greatly enhanced the ellipticity of 1g in methanol
but did not cause any shift of the curve in the wavelength. This
intensified absorbance should contribute well to the much higher
enantioselectivity of 1g in methanol with the additive benzoic
acid.
30
30
a 0.2 mmol reaction at room temperature unless noted otherwise.
b Hydroxyacetone/solvent 2/3 (v/v). c Determined by chiral HPLC. d Ee
of anti isomer, determined by chiral HPLC. e No peptide was used as
catalyst. f Reaction at 0 °C. g Reaction at -10 °C.
type II ꢀ-turn structure that is in good accord with the
investigation on the CD curves. The ꢀ-turn for tetrapeptide 1g
is supported by the observation of the strong NH (Gly)-NH
(Leu) NOE and the CRH (Pro)-NH (Leu) NOE. In addition, a
type II ꢀ-turn can result from the characterized strong CRH (Pro)-
NH (Gly) NOE.22a,23 A similar tendency with benzoic acid (1g:
PhCOOH ) 1:2) as the additive can also be observed. And the
main difference between the spectra with and without benzoic
acid in methanol is that the strong signals from benzoic acid in
the benzene ring region made the spectra more confusing. It is
surprising that no cis rotamer was noted in the NMR.
The NOE experiments (see Figures S2 and S3 in the
Supporting Information) in methanol indicate the presence of a
(22) (a) Imperiali, B.; Fisher, S. L.; Moats, R. A.; Prins, T. J. J. Am. Chem.
Soc. 1992, 114, 3182. (b) Brahms, S.; Brahms, J. J. Mol. Biol. 1980, 138, 149.
(c) Dutt, A.; Dutta, A.; Mondal, R.; Spencer, E. C.; Howard, J. A. K.; Pramanik,
A. Tetrahedron 2007, 63, 10282.
(23) (a) Raghothama, S. R.; Awasthi, S. K.; Balaram, P. J. Chem. Soc., Perkin
Trans. 2 1998, 137. (b) Morikis, D.; Roy, M.; Sahu, A.; Troganis, A.; Jennings,
P. A.; Tsokos, G. C.; Lambris, J. D. J. Biol. Chem. 2002, 277, 14942.
4816 J. Org. Chem. Vol. 74, No. 13, 2009

N-Primary-Amine-Terminal ꢀ-Turn Tetrapeptides
TABLE 4. Aldol Reaction of Hydroxyacetone with Aromatic
Aldehydesa
J ) 8.8 Hz, 1H), 4.33-4.36 (dd, J ) 6.4 Hz, J ) 9.2 Hz, 1H),
3.85-3.89 (m, 1H), 3.53-3.59 (m, 1H), 2.06-2.22 (m, 2H),
1.93-2.04 (m, 3H), 1.39-1.48 (m, 9H), 0.96-0.98 (d, J ) 6.8
Hz, 3H), 0.90-0.92 (d, J ) 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 171.6, 170.9, 155.7, 135.7, 128.6, 128.5, 128.2, 128.0,
79.4, 66.7, 58.9, 56.8, 47.1, 31.5, 29.1, 28.3, 24.6, 19.6, 17.3; ESI-
MS calcd for [C22H32N4O5 + H+] 405.2, found 405.2, and calcd
for [C22H32N4O5 + Na+] 427.2, found 427.2.
entry
R1
time (h)
yield (%)b
anti/sync
ee (%)d
General Procedure for Synthesis of Peptides 4d-e.25 To a
solution of Boc-Gly-OH (2 g, 11.4 mmol) in THF (40 mL) was
added NMM (1.26 mL, 12.54 mmol) dropwise at -15 °C, followed
by i-BuOCOCl (1.64 mL, 12.54 mmol). After 3-5 min, a mixture
of Leu-OBn ·TOSOH (4.48 g, 11.4 mmol) and NMM (1.26 mL,
12.54 mmol) in DMF (6 mL) was added dropwise. The mixture
was stirred at -15 °C for 30 min and then for 4 h at room
temperature. The insoluble byproducts formed were filtered off and
the filtrate was evaporated to dryness. The remaining oily residue
was dissolved in EtOAc and extracted successively with saturated
aqueous NaHCO3, water, aqueous HCl (1.0 M), and brine. The
organic layer was then dried over anhydrous Na2SO4, filtered, and
1
2
3
4
5
6
4-NO2
3-NO2
2-NO2
4-CF3
2-CF3
2-Cl
30
72
72
42
72
60
>99
89
85
57
42
56
74/26
47/53
63/37
63/37
63/37
60/40
87
62
91
68
81
73
a 0.2 mmol reaction in 0.6 mL of CH3CN and 0.4 mL of
hydroxyacetone at -10 °C. b Isolated yields. c Determined by chiral
HPLC. d Ee of anti isomer, determined by chiral HPLC.
In summary, several N-primary-amine-terminal tetrapeptides
with ꢀ-turn nucleating segments were designed and synthesized,
and were first applied to catalyze the asymmetric aldol reaction.
Tetrapeptide 1g, based on the conformationally highly restricted
sequence D-Pro-Gly, was an efficient organocatalyst when it
formed a stable ꢀ-turn secondary structure in methanol. It could
catalyze the highly enantioselective reactions of acetone with
aldehydes in the addition of benzoic acid. The solvents not only
influenced the enantioselectivity but also the asymmetric induc-
tion of the reaction. A strongly polar solvent such as MeOH
could give the (R)-aldols, whereas apolar and weakly polar
solvents such as DCE afforded the (S)-aldols. Both of the CD
and NOESY spectra showed the presence of the clear ꢀ-turn
secondary structure in MeOH, which should contribute to (R)-
aldols and high enantioselectivity. In the aldol reaction of
hydroxyacetone, however, the solvents only affected the values
of the enantioselectivities but not the asymmetric inductions.
Therefore secondary structures of the tetrapeptide which are
greatly dependent upon the varied solvents could not surprisingly
have effects on the asymmetric induction on account of the
strong behavior of hydroxyacetone in the reaction. The peptide
1g harvested (S,S)-aldols in MeCN with the additive BINOL,
and achieved the highest enantioselectivity of the branched
isomeric products of hydroxyacetone with peptidic organocata-
lyts. Interestingly, the same peptidic catalyst was used to
catalyze the reactions of different ketones, acetone and hy-
droxyacetone, but afforded different configuration aldols.
concentrated in vacuo, to provide 4e as an oil (4.34 g, 100%). [R]20
D
-4 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.33-7.39 (m,
5H), 6.78-6.80 (d, J ) 7.2 Hz, 1H), 5.36-5.38 (t, J ) 4.8 Hz,
1H), 5.15 (m, 2H), 4.68 (m, 1H), 3.81-3.85 (dd, J ) 5.2 Hz, J )
11.2 Hz, 2H), 1.50-1.67 (m, 3H), 1.45 (s, 9H), 0.90-0.91 (m,
6H); ESI-MS calcd for [C20H30N2O5 + H+] 379.2, found 379.3,
and calcd for [C20H30N2O5 + Na+] 401.2, found 401.3.
General Procedure for Synthesis of Peptides 6a-f. Deben-
zylation was carried out by dissolving 4a (2 g, 4.95 mmol) in
MeOH, successively introduced with Pd/C (10 m%, 200 mg).
Stirring under H2 atmosphere continued for 2 h. After this period
the Pd/C residue was filtered and the collected solvent was
evaporated to provide 5a (1.56 g, quantitative). This compound
was directly used in the next synthetic step with no further
purification.
To the dipeptide 4e (2 g, 5.29 mmol) was added a solution of
TFA (5.3 mL) in CH2Cl2 (5.3 mL) at 0 °C. After 2 h of stirring the
acid was removed under reduced pressure. The remaining oily
residue was dissolved in CH2Cl2, and then adjusted to about pH
10.0 with aqueous NaOH (1.0 M). The organic layer was separated,
and the aqueous layer was re-extracted three times with CH2Cl2.
Then the combined organic layers were washed with a little brine,
dried with anhydrous Na2SO4, and condensed to dryness in vacuo
to afford 5e as an oil (1.40 g, 95%). This compound was directly
used in the next synthetic step with no further purification.
To a solution of 5a (1.56 g, 4.95 mmol) in THF (20 mL) was
added NMM (0.60 mL, 5.45 mmol) dropwise under an argon
atmosphere at -15 °C, followed by i-BuOCOCl (0.71 mL, 5.45
mmol). After 5 min, a mixture of 5e (1.38 g, 4.95 mmol) and NMM
(0.60 mL, 5.45 mmol) in THF (5 mL) was added dropwise. The
mixture was stirred at the same temperature for 30 min successively
at room temperature for 4 h. The insoluble byproducts formed were
filtered off and the filtrate evaporated to dryness. The remaining
oily residue was dissolved in EtOAc and extracted successively
with saturated aqueous NaHCO3, water, aqueous HCl (1.0 M), and
saturated brine and then dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo. The resulting residue was recrystallized with
petroleum ether and ethyl acetate to give the desired product 6f as
a white crystal (2.05 g, 72%). Mp 123.5-125.5 °C; [R]20D -15 (c
Experimental Section
General Procedure for Synthesis of Peptides 4a-c.24 Boc-
Val-OH (1.8 g, 8.27 mmol) was stirred with HOBt (1.36 g, 9.1
mmol) and DIC (1.41 mL, 9.1 mmol) in THF (25 mL) at 0 °C for
0.5 h. A mixture of D-Pro-OBn ·HCl (2 g, 8.27 mmol) and NMM
(1 mL, 9.1 mmol) in DMF (4 mL) was added, and the reaction
was stirred for another 48 h. The insoluble byproduct was filtered
off and the filtrate evaporated to dryness. The remaining oily residue
was dissolved in EtOAc, and extracted successively with saturated
aqueous NaHCO3 solution, water, aqueous HCl (1.0 M), and brine.
The organic phase was dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo. The resulting residue was recrystallized with
1
0.7, CHCl3); H NMR (400 MHz, CDCl3) δ 7.30-7.36 (m, 5H),
7.23-7.24 (m, 1H), 5.32-5.34 (d, J ) 6.8 Hz, 1H), 5.13-5.20
(dd, J ) 12.4 Hz, J ) 14.8 Hz, 2H), 4.59-4.64 (m, 1H), 4.47-4.50
(t, J ) 6.0 Hz,1H), 4.14-4.20 (dd, J ) 7.2 Hz, J ) 16.8 Hz, 1H),
4.07 (m, 1H), 3.94-3.98 (m, 1H), 3.56-3.65 (m, 2H), 2.16-2.21
(m, 2H), 1.99-2.09 (m, 2H), 1.90-1.95 (m, 1H), 1.61-1.76 (m,
3H), 1.40 (s, 9H), 1.00-1.01 (d, J ) 6.8 Hz, 3H), 0.95-0.97 (d,
petroleum ether and ethyl acetate to give the dipeptide 4a as a white
crystal (2.5 g, 75%). Mp 109 °C; [R]20 +47 (c 0.76, CHCl3); H
1
D
NMR (400 MHz, CDCl3) δ 7.32-7.39 (m, 5H), 5.23-5.25 (d, J
) 10.8 Hz, 1H), 5.11-5.20 (m, 2H), 4.47-4.50 (dd, J ) 3.2 Hz,
(24) Larroque, A.-L.; Dubois, J.; Thoret, S.; Aubert, G.; Chiaroni, A.; Gue´ritte,
F.; Gue´nard, D. Bioorg. Med. Chem. 2007, 15, 563.
(25) Marshall, G. R.; Beusen, D. D.; Kociolek, K.; Redlinski, A. S.; Leplawy,
M. T.; Pan, Y.; Schaefer, J. J. Am. Chem. Soc. 1990, 112, 963.
J. Org. Chem. Vol. 74, No. 13, 2009 4817

Wu et al.
J ) 6.8 Hz, 3H), 0.88-0.92 (m, 6H); 13C NMR (100 MHz, CDCl3)
δ 172.6, 171.7, 169.0, 156.9, 135.7, 128.4, 128.0, 127.8, 80.3, 66.4,
61.0, 58.2, 50.7, 47.6, 43.1, 40.7, 30.1, 29.2, 28.1, 24.6, 23.4, 22.8,
21.7, 19.1, 18.8; ESI-MS calcd for [C30H46N4O7 + H+] 575.3, found
575.3.
CH2Cl2. Then the combined organic layers were washed with a
little brine, dried with anhydrous Na2SO4, and condensed to dryness
in vacuo to give the desired product 1i (0.35 g, yield 87%). [R]20
D
+48 (c 1.0, CHCl3); FT-IR 3297, 3068, 2958, 2874, 1744, 1668,
1
1626 cm-1; H NMR (400 MHz, CDCl3) δ 7.56-7.57 (m, 1H),
General Procedure for Synthesis of Peptides 6g,h.26 Com-
pound 7 was quantitatively prepared according to the same
procedure as peptide 5a and directly used in the next step without
further purification. To a solution of 7 (803 mg, 2.38 mmol) in
THF (10 mL) was added NMM (0.29 mL, 2.62 mmol) dropwise
under an argon atmosphere at -15 °C, followed by i-BuOCOCl
(0.34 mL, 2.62 mmol). After 5 min, a mixture of Ala-OBn ·TOSOH
(834 mg, 2.38 mmol) and NMM (0.29 mL, 2.62 mmol) in DMF (2
mL) was added dropwise. The mixture was stirred at the same
temperature for 30 min successively at room temperature for 4 h.
The insoluble byproducts formed were filtered off and the filtrate
was evaporated to dryness. The remaining oily residue was
dissolved in EtOAc and extracted successively with saturated
aqueous NaHCO3, water, aqueous HCl (1.0 M), and brine and then
dried over anhydrous Na2SO4, filtered, and concentrated in vacuo.
The resulting residue was recrystallized with petroleum ether and
7.42-7.44 (d, J ) 7.2 Hz, 1H), 4.49-4.55 (m, 1H), 4.42-4.46
(m, 1H), 4.21-4.27 (dd, J ) 7.6 Hz, J ) 17.2 Hz, 1H), 3.81-3.87
(m, 1H), 3.69 (s, 3H), 3.64-3.65 (d, J ) 5.2 Hz, 1H), 3.54-3.60
(m, 1H), 3.27-3.28 (d, J ) 6.8 Hz, 1H), 2.46 (br, 2H), 1.98-2.46
(m, 4H), 1.85-1.90 (m, 1H), 1.69-1.82 (m, 2H), 1.59-1.64 (m,
1H), 0.90-0.99 (m, 12H); 13C NMR (100 MHz, CDCl3) δ 175.2,
174.0, 171.9, 169.5, 61.0, 58.9, 52.1, 50.7, 47.4, 42.7, 40.4, 31.9,
29.0, 24.8, 24.7, 22.9, 21.6, 19.8, 17.5; HRMS calcd for
[C19H34N4O5 + H+] 399.2602, found 399.2604.
General Procedure for Asymmetric Aldol Reaction of
Acetone and Aldehydes. Tetrapeptide 1g (0.04 mmol) and benzoic
acid (0.08 mmol) were added into a mixture of aldehyde (0.2 mmol)
and dry ketone (0.4 mL) in MeOH (0.6 mL). The reaction was
stirred to completion monitored by TLC, and then saturated aqueous
NH4Cl (2 mL) was added to quench the reaction. Subsequently,
the mixture was extracted with EtOAc three times. The organic
layers were combined, dried with anhydrous Na2SO4, concentrated
in vacuo, and purified by preparative TLC or column to yield the
desired aldol product.
ethyl acetate to give the desired product 6g as a white crystal (734
1
mg, 58%). Mp 129-131 °C; [R]20 -3 (c 0.3, CH2Cl2); H NMR
D
(400 MHz, CDCl3) δ 7.29-7.41 (m, 6H), 5.33-5.35 (d, J ) 6.4
Hz, 1H), 5.11-5.17 (m, 2H), 4.56-4.61 (m, 1H), 4.50-4.52 (m,
1H), 3.96-4.15 (m, 3H), 3.65-3.70 (dd, J ) 6.0 Hz, J ) 17.6 Hz,
1H), 3.56-3.62 (dd, J ) 8.0 Hz, J ) 17.2 Hz, 1H), 1.91-2.22 (m,
5H), 1.44-1.46 (d, J ) 7.2 Hz, 3H), 1.38-1.40 (m, 9H), 1.00-1.02
(m, 3H), 0.95-0.97 (d, J ) 7.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 172.7, 172.6, 171.7, 168.8, 155.8, 135.6, 128.5, 128.2,
127.9, 80.4, 66.6, 61.0, 58.3, 48.1, 47.7, 43.1, 30.3, 29.1, 28.3, 28.2,
24.7, 19.2, 18.8, 17.9; ESI-MS calcd for [C27H40N4O7 + H+] 533.3,
found 533.2, and calcd for [C27H40N4O7 + Na+] 555.3, found 555.2.
General Procedure for Synthesis of Peptides 1a-h. To the
tetrapeptide 6f (1.93 g, 3.37 mmol) was added a solution of TFA
(3.4 mL) in CH2Cl2 (3.4 mL) at 0 °C. After 4 h of stirring, the acid
was removed under reduced pressure. The remaining oily residue
was dissolved in CH2Cl2, and then adjusted to about pH 10.0 with
aqueous NaOH (1.0 M). The organic layer was separated, and the
aqueous layer was re-extracted three times with CH2Cl2. Then the
combined organic layers were washed with a little brine, dried with
anhydrous Na2SO4, and condensed to dryness in vacuo (1.47 g,
3.10 mmol, yield 92%). The remaining residue was dissolved in
MeOH, introduced with Pd/C (10 mol %, 147 mg). Stirring under
H2 atmosphere was continued for 2 h. After this period, Pd/C was
filtered and the collected solvent was evaporated. The obtained
white solid was refluxed in ether for 10 min, then filtered
(R)-4-Hydroxy-4-(4-nitrophenyl)butan-2-one (2a):6,8 yield 58%;
1
95% ee; [R]20 +45 (c 1.0, CHCl3); H NMR (200 MHz, CDCl3)
D
δ 8.16-8.23 (m, 2H), 7.52-7.58 (m, 2H), 5.24-5.30 (m,1H), 3.60
(br, 1H), 2.84-2.88 (m, 2H), 2.23 (s, 3H); ee was determined by
HPLC with a AS-H column (hexane:2-propanol ) 95:5), 1.0 mL/
min, tR ) 13.48 min for (R)-enantiomer (major) and 18.97 min for
(S)-enantiomer (minor).
General Procedure for Asymmetric Aldol Reaction of Hy-
droxyacetone and Aldehydes. Peptide 1g (0.04 mmol) and (S)-
BINOL (0.04 mmol) were added to a solution of aldehyde (0.2
mmol) in CH3CN (0.6 mL). After the mixture was cooled to -10
°C, hydroxyacetone (0.4 mL) was added. The reaction was stirred
to completion monitored by TLC, and then saturated aqueous NH4Cl
(2 mL) was added to quench the reaction. Subsequently, the mixture
was extracted with EtOAc three times. The organic layers were
combined, dried with anhydrous Na2SO4, concentrated in vacuo,
and purified by preparative TLC or column to yield the desired
aldol product.
(3S,4S)-4-(4-Nitrophenyl)-3,4-dihydroxybutan-2-one (3a):21
yield 99% (anti and syn); anti/syn 74/26; 87% ee (anti); [R]20D -12
(c 2.0, MeOH); (anti-3a) 1H NMR (400 MHz, CDCl3) δ 8.24-8.26
(m, 2H), 7.61-7.63 (d, J ) 8.4 Hz, 2H), 5.10-5.11 (d, J ) 3.2
Hz, 1H), 4.48 (m, 1H), 3.75-3.76 (d, J ) 4.0 Hz, 1H), 3.14 (s,
1H), 2.03 (s, 3H); (syn-3a) 1H NMR (400 MHz, CDCl3) δ
8.24-8.26 (m, 2H), 7.61-7.63 (d, J ) 8.4 Hz, 2H), 5.24 (s, 1H),
4.42 (s, 1H), 3.78-3.79 (d, J ) 4.4 Hz, 1H), 2.93-2.94 (d, J )
7.2 Hz, 1H), 2.38 (s, 3H); diastereomeric ratio and enantiomeric
excess determined by HPLC with a AD-H column (hexane:2-
propanol ) 70:30), 1.0 mL/min, tR ) 5.41 (major for S,S isomer)
and 5.96 (minor for R,R isomer) min for the anti isomers, 6.55 and
8.10 min for the syn isomers.
immediately to provide 1g (1.06 g, 89%). Mp 152-154 °C; [R]20
D
+58 (c 0.85, H2O); FT-IR (solid) 3248, 2956, 2866, 1690, 1650,
1558, 1516 cm-1; 1H NMR (300 MHz, D2O) δ 4.30-4.33 (m, 1H),
4.06-4.09 (d, J ) 8.7 Hz, 2H), 3.81 (s, 1H), 3.62-3.72 (m, 2H),
3.51-3.59 (m, 1H), 2.13-2.22 (m, 2H), 1.86-1.93 (m, 3H),
1.40-1.55 (m, 3H), 0.91-0.93 (d, J ) 6.9 Hz, 3H), 0.83-0.85 (d,
J ) 6.9 Hz, 3H), 0.73-0.75 (d, J ) 5.1 Hz, 3H), 0.69-0.71 (d, J
) 5.1 Hz, 3H); 13C NMR (75 MHz, D2O) δ 179.0, 174.3, 170.3,
169.0, 61.1, 57.1, 53.5, 48.0, 42.3, 40.5, 29.2, 28.6, 24.5, 24.2, 22.4,
20.4, 17.9, 15.9; ESI-MS calcd for [C18H32N4O5 + H+] 385.2, found
385.2, calcd for [C18H32N4O5 + Na+] 407.2, found 407.2; HRMS
calcd for [C18H32N4O5 + H+] 385.2445, found 385.2438.
Acknowledgment. We thank the NSFC (No. 20672051) for
financial support. And we are greatly thankful to Dr. Xuan Shao
for her assistance on the interpretation of the NOESY spectra
and Beijing Nuclear Magnetic Resonance Center of Peking
University for measurement of them.
General Procedure for Synthesis of Peptides 1i. To the
tetrapeptide 6h (0.5 g, 1 mmol) was added a solution of TFA (1
mL) in CH2Cl2 (1 mL) at 0 °C. After the mixture was stirred for
4 h, the acid was removed under reduced pressure. The remaining
residue was dissolved in CH2Cl2, then the pH was adjusted to 10.0
or so with aqueous ammonia (2.0 M). The organic layer was
separated, and the aqueous layer was re-extracted three times with
Supporting Information Available: CD spectra, 2D NMR
(NOESY), characterization of compounds, and spectra (1H
NMR, 13C NMR, and HPLC). This material is available free of
charge via the Internet at http://pubs.acs.org.
(26) Luppi, G.; Lanci, D.; Trigari, V.; Garavelli, M.; Garelli, A.; Tomasini,
C. J. Org. Chem. 2003, 68, 1982.
JO9005766
4818 J. Org. Chem. Vol. 74, No. 13, 2009