Short α/β-peptides as catalysts for intra- and intermolecular aldol reactions

Article abstract of DOI:10.1021/jo800168h

(Chemical Equation Presented) Short α/β-peptides, containing conformationally restricted cis-β-aminocyclopropylcarboxylic acid units as turn-inducing elements, have been found to be efficient catalysts for inter-and intramolecular aldol reactions. The tripeptide H-(L)-Pro--(L)-Pro-OH was identified to perform especially well in homogeneous and heterogeneous aqueous solutions as well as in organic solvents.

Full text of DOI:10.1021/jo800168h

Short r/â-Peptides as Catalysts for Intra- and
Intermolecular Aldol Reactions
Valerio D’Elia, Hans Zwicknagl, and Oliver Reiser*
Institut fu¨r Organische Chemie, UniVersita¨t Regensburg,
UniVersita¨tsstr. 31, 93053 Regensburg, Germany
FIGURE 1. Transition-state model for the (L)-proline-catalyzed aldol
reaction (left) and the cis-â-ACC enantiomers 2 and 1 used in this
study.
OliVer.Reiser@chemie.uni-regensburg.de
ReceiVed January 22, 2008
ties, we set out to explore if the â-ACCs would also be useful
building blocks for peptidic organocatalysts. We would like to
disclose here short R,â-peptides containing the unnatural cis-
â-ACCs 2 and 1 (Figure 1 and Scheme 1) that allow inter-
and intramolecular aldol reactions to be carried out with high
yields and enantioselectivity.
SCHEME 1. Standard Reaction Scheme for the Synthesis
of Peptides with Central and Terminal â-ACC Units
Short R/â-peptides, containing conformationally restricted
cis-â-aminocyclopropylcarboxylic acid units as turn-inducing
elements, have been found to be efficient catalysts for inter-
and intramolecular aldol reactions. The tripeptide H-(L)-
Pro-2-(L)-Pro-OH was identified to perform especially well
in homogeneous and heterogeneous aqueous solutions as well
as in organic solvents.
The aldol reaction represents one of the most powerful tools
available for C-C bond formation. In the last years several
efforts have been directed to create metal-free catalysts that
would allow high yield and selectivity for this reaction. With
the pioneering work of Hajos and Parrish and Eder et al.,1 it
became apparent that (L)-proline arguably represents the best
example of a naturally available organocatalyst. Its unique mode
of action, i.e., both the amino and the carboxylic acid func-
tionality of the catalyst cooperate in activating and arranging
the reagents2 (Figure 1), recalls the biological activity of the
enzyme type I aldolase.3 However, proline does not currently
represent the most efficient organocatalyst for this process
because of the solvent choice necessary (DMSO) to be an
effective catalyst.4
â-aminocyclopropane carboxylic acids (â-ACCs) have proved
to greatly stabilize secondary structures even in short peptides
when combined with natural R-amino acids, which has led to
the synthesis of a novel class of foldamers5 as well as to ligands
with high affinity and selectivity for specific neuropeptide Y
and integrin receptors.6 On the basis of these structural proper-
Taking the excellent results of Wennemers and co-workers7
into account, who demonstrated the benefits of (L)-proline in
tripeptide catalysts for the aldol reaction, we concentrated on
combinations of at least one of this residue with 2 or 1.
The shelf-stable building block 2 required for the incorpora-
tion of â-ACC into peptides is readily accessible from N-Boc-
pyrrole in either enantiomeric form.8 Since we could not forsee
which â-ACC enantiomer would be more effective in combina-
tion with naturally occurring R-amino acids, we wanted to
investigate peptides with both 2 or 1 being incorporated.
Therefore, it was more efficient to synthesize dipeptides using
the racemic rather than the enantiomerically pure â-ACCs
following the in situ coupling strategy developed by us9 and
separate the resulting diastereomers by column chromatography
(Scheme 1). Subsequent deprotection at the C-terminus and
coupling with amino acids or peptides cleanly resulted in the
corresponding tri- and tetrapeptides.
(6) (a) Koglin, N.; Zorn, C.; Beumer, R.; Cabrele, C.; Bubert, C.; Sewald,
N.; Reiser O.; Beck-Sickinger, A. G. Angew. Chem., Int. Ed. 2003, 42,
202. (b) Urman, S.; Gaus, K.; Yang, Y.; Strijowski, U.; Sewald, N.; De
Pol, S.; Reiser, O. Angew. Chem., Int. Ed. 2007, 46, 3976.
(7) (a) Krattinger, P.; Kovasy, R.; Revell, J. D.; Ivan, S.; Wennemers,
H. Org. Lett. 2005, 7, 1101. (b) (b) Revell, J. D.; Wennemers, H.
Tetrahedron 2007, 63, 8420.
(1) (a) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615. (b)
Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. 1971, 10, 496.
(2) (a) Hoang, L.; Bahmanyar, S.; Houk, K. N.; List, B. J. Am. Chem.
Soc. 2003, 125, 16. (b) Bahmanyar, S.; Houk, K. N.; Martin, H. J.; List, B.
J. Am. Chem. Soc. 2003, 125, 2475.
(3) Jarvo, E. R.; Miller, S. J. Tetrahedron 2002, 58, 2481.
(4) List, B.; Lerner, R. A.; Barbas C. F., III J. Am. Chem. Soc. 2000,
122, 2395.
(5) (a) De Pol, S.; Zorn, C.; Klein, C. D.; Zerbe, O.; Reiser, O. Angew.
Chem., Int. Ed. 2004, 43, 511.
(8) (a) Gheorghe, A.; Schulte, M.; Reiser, O. J. Org. Chem. 2006, 71,
2173. (b) Beumer, R.; Bubert, C.; Cabrele, C.; Vielhauer, O.; Pietzsch, M.;
Reiser, O. J. Org. Chem. 2000, 65, 8960.
(9) (a) Bubert, C.; Cabrele, C.; Reiser, O. Synlett 1997, 827. (b) Voigt,
J.; Noltemeyer, M.; Reiser, O. Synlett 1997, 202.
10.1021/jo800168h CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/15/2008
3262
J. Org. Chem. 2008, 73, 3262-3265

TABLE 1. Aldol Reaction between 9 and 10 Catalyzed by (L)-Pro
and â-ACC-Containing Peptidic Catalysts
TABLE 2. Aldol Reaction between 9 and 10 Catalyzed by (L)-Pro
and Pro-2-Pro, Pro-Pro-1a
catalysta
H-XXX-OH
yield
(%)
ee
(%)
entry
R
solventb
catalyst
H-XXX-OH
yieldb
(%)
50c
48
79(S)
76(R)
80(S)
68(R)
84(S)
80(R)
82(S)
72(R)
88(S)
91(S)
88(S)
78(R)
82(S)
41(R)
entry
1c
2
3
4
5
6
7
8
solventa
ee (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Ph
Ph
Pro-Pro-1
Pro-2-Pro
Pro-Pro-1
Pro-2-Pro
Pro-Pro-1
Pro-2-Pro
Pro-Pro-1
Pro-2-Pro
Pro-Pro-1
Pro-2-Pro
Pro-Pro-1
Pro-2-Pro
Pro-Pro-1
Pro-2-Pro
E
B
E
B
E
B
E
B
E
B
E
B
E
B
Pro
Pro
Pro
Pro
DMSO
A
B
C
E
A
C
A
C
C
C
A
B
C
D
E
C
C
E
C
E
68
74
98
95
68
56
47
29
45
77
89
99
89
72
95
53
70
59
59
48
79
86
75
83
96
66
36
76
58
76(R)
53(R)
0
o-Cl-Ph
o-Cl-Ph
p-Cl-Ph
p-Cl-Ph
o-Br-Ph
o-Br-Ph
o-NO2-Ph
o-NO2-Ph
p-NO2-Ph
p-NO2-Ph
c-C6H11
91d
80
42c
43
0
Pro
61(R)
14
84d
86
Pro-1
Pro-1
Pro-2
Pro-2
0
88
64(R)
65(R)
6(R)
13(R)
70(R)
78(R)
74(R)
71(R)
29(R)
62(R)
73(R)
64(S)
0
73(S)
88(S)
83(S)
57(S)
51(R)
37(S)
74(R)
33(S)
0
82
9
86c
89
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
Pro-1-Pro
Pro-1-Asp
Pro-2-Pro
Pro-2-Pro
Pro-2-Pro
Pro-2-Pro
Pro-2-Pro
Pro-2-Asp
Pro-2-Glu
Pro-Pro-2
Pro-Pro-2
Pro-Pro-1
Pro-Pro-1d
Pro-Pro-1d,e
Pro-Pro-1
Pro-â-Ala-Pro
Pro-â-Ala-Pro
Pro-2-Pro-1
Pro-1-Pro-Pro
Pro-1-Pro-Pro
57
57
c-C6H11
a Reactions were carried out at 25 °C, for 24 h, using 0.2 mmol 10, 20
mol % of catalyst in 2 mL of solvent. b Cf. Table 1. c At 10 °C. d At 5 °C.
For aldol reactions with aromatic ketones and acetone, the
â-ACC-containing peptide catalysts gave generally good yields
and selectivities with both catalysts tested, giving rise to the
aldol products with opposite absolute stereochemistry. In
contrast, for cyclohexylcarbaldehyde, H-Pro-Pro-1-OH gave
considerably better results (Table 2). Conveniently, the peptide
catalyst could be recovered quantitatively with excellent purity
in all cases by lyophilization after the evaporation of acetone
and extraction of 11 with ethyl acetate from the aqueous phase.
The catalyst H-Pro-2-Pro-OH was subsequently tested in
the aldol reaction between aromatic aldehydes and some
representative cyclic ketones (Table 3), using either homoge-
neous water/ketone solutions that had already proved to be
effective for this catalyst or heterogeneous water containing
mixtures that have been reported in the literature as effective
media for this process.14 Neat ketones have been employed as
solvents as well, to investigate the ability of water to enhance
the catalytic performance.
E
E
C
C
E
C
E
C
a All reactions were carried out at 25 °C in 24 h, using 0.2 mmol 10a
and 20 mol % of catalyst in 2 mL of solvent unless noted otherwise. A,
acetone; B, acetone/water 10:1 (v/v); C, acetone/water 5:1 (v/v); D, acetone/
water 3:1 (v/v); E, CHCl3/acetone 2:1 (v/v). b Isolated yields, ee determined
by chiral HPLC or chiral GC (after converting the product to its
corresponding trimetylsilylether). c Taken from ref 3. d Reaction carried out
at 0 °C. e With 5 mol % of catalyst.
As a benchmark, we decided to test our peptides as catalysts
for the aldol reaction of acetone and p-nitrobenzaldehyde (Table
1). From screening a variety of di, tri-, and tetrapeptides, it
became apparent that tripeptides with â-ACC units appeared
to be optimal in length. H-Pro-2-Pro-OH and H-Pro-Pro-
1-OH were found to be particularly effective, giving rise to
11a in up to 88% ee (entry 22). It was important to note that
both the conformational rigidity as well as the absolute config-
uration of the â-ACCs was a decisive factor. Using â-alanine
or 1 as the central or 2 as the terminal building block in com-
bination with (L)-amino acids gave inferior results; representa-
tive examples are shown in Table 1, entries 10-26. Interestingly,
the peptide Pro-2-Pro is an effective asymmetric10 catalyst11
in homogeneous aqueous12 solution without the necessity of
employing additives (entry 13-15), contrasting with proline
(entries 3 and 4) and comparing well to other organocatalysts
that have been investigated in such media for the title reaction.13
With H-Pro-2-Pro-OH in acetone/water and H-Pro-Pro-
1-OH in acetone/chloroform identified as promising catalysts
for aldol reactions, their scope was further explored.
High selectivities and good yields have been obtained in the
case of cyclic six-membered ketones. A substantial improvement
of selectivity for cyclohexanone as substrate was observed by
switching from homogeneous to heterogeneous aqueous reaction
conditions. However, the reactions proceeded slower in such
reaction media to the point that no reaction was observed
between p-chlorobenzaldehyde and acetone (entry 5). Cyclo-
pentanone proved to be a highly reactive, but less selective
substrate.
(11) (a) Reymond, J.-L.; Chen, Y. J. Org. Chem. 1995, 60, 6970. (b)
Dickerson, T.; Janda, K. D. J. Am. Chem. Soc. 1995, 124, 3220.
(12) For recent discussions of organic reactions being catalyzed in
aqueous solvents: (a) Blackmond, D. Angew. Chem., Int. Ed. 2007, 46,
3798. (b) Brogan, A. P.; Dickerson, T. J.; Janda, K. D. Angew. Chem., Int.
Ed. 2006, 45, 8100. (c) Hayashi, Y. Angew. Chem., Int. Ed. 2006, 45, 8103.
(13) (a) Guizzetti, S.; Benaglia, M.; Raimondi, L.; Celentano, G. Org.
Lett. 2007, 9, 1247. (b) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe,
K.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128, 734. (c)
Cordova, A.; Zou, W.; Dziedzic, P.; Ibrahem, I.; Reyes, E.; Xu, Y. Chem.s
Eur. J. 2006, 12, 5383.
(14) (a) Gryko, D.; Saletra, W. J. Org. Biomol. Chem. 2007, 5, 2148.
(b) Wu, X.; Jiang, Z.; Shen, H.-M.; Lu, Y. AdV. Synth. Catal. 2007, 349,
812. (c) Jung, Y.; Marcus, R. A. J. Am. Chem. Soc. 2007, 129, 5492. (d)
Amedjkouh, M. Tetrahedron: Asymmetry 2007, 18, 390.
(10) Aratake, S.; T- Itoh, T. O.; Usui, T.; Shoji, M.; Hayashi, Y. Chem.
Commun. 2007, 2524.
J. Org. Chem, Vol. 73, No. 8, 2008 3263

TABLE 3. Reaction between Aromatic aldehydes and Cyclic
Ketones
FIGURE 2. Low-energy structure of H-Pro-2-Pro-OH having a cis-
amide bond at the C-terminal proline.
ketone/
water
d.r.
anti/
sync
ee
ee
yield
(%)b
(%)
(%)
entry
12
R
(v/v)a
antic
sync
rivaling the use of catalytic antibodies with respect to selectiv-
ity.18 From the â-ACC-containing peptides, again the tripeptides
and particularly H-Pro-2-Pro-OH proved to be the most
effective catalysts.
1
2
3
4
5
6
7
8
9
12a
12a
12a
12a
12a
12a
12a
12a
12a
12b
12b
12b
12b
12c
12c
p-NO2
p-NO2
p-NO2
p-Cl
p-Cl
o-Br
o-Br
o-Cl
o-Cl
p-NO2
p-NO2
p-NO2
p-NO2
p-NO2
p-NO2
neat
20:1
10:1d
20:1
10:1d
20:1
10:1d
20:1
10:1d
neat
20:1
10:1
5:1d
76
96
3/1
2/1
6/1
9/1
66
87
95
91
10
73
99
66
75e
50
e
The cyclization of 14b was achieved with 92% ee (Table 4,
entry 3), coming close to the level that is reached with 16 (entry
2), but notably, high yields were already reached with 10 mol
% catalyst within 1 day at room temperature. Good enantiose-
lectivites were also observed in aqueous solvents (entry 4);
however, the rate was considerably diminished, while in DMF,
DMSO, or acetonitrile the reaction did not proceed at all.
The remarkable catalytic properties of the peptide H-Pro-
2-Pro-OH suggested the existence of privileged conformations
in which the C- and N-termini are close to each other. Indeed,
this is supported by NMR studies in methanol-d3, which revealed
the presence of two rotamers around the C-terminal proline
amide bond in a ratio of 3:1. On the basis of the analysis of
NOE signals19 and 13C shifts20 of the â- and γ-carbons of
proline, the minor, but nevertheless significantly21 populated
rotamer was assigned to have a cis-proline bond being in
agreement with the low-energy, turn-like structure calculated
by molecular modeling with the Spartan program package22
(Figure 2).
72
60e
63
40e
46
99
90
70
71
80
40/1
90/1
45/1
70/1
1/2
1/3
1/3
1/2
1/2
93
95
90
98
46
56
61
68
83
91
10f
11f
12f
13f
14
15
49
37
40
87
76
20:1
3:1
3/2
a Reactions were carried out at 25 °C, for 24 h, using 0.15 mmol of
aldehyde, 20 mol % of catalyst in 0.4 mL of ketone, and the proportional
amount of water. b Isolated after column chromatography. c Determined
through chiral GC (after converting the product to its corresponding
trimetylsilylether). d Heterogeneous reaction mixture. e Reaction in 48 h.
f With 10 mol % catalyst.
TABLE 4. Intramolecular Aldol Reactions of 14a
In conclusion, novel peptide catalysts based on conforma-
tionally highly restricted â-aminocyclopropanecarboxylic acids
were identified. Noteworthy, H-Pro-2-Pro-OH is effective in
inter- and intramolecular aldol reactions either in organic or in
homogeneous aqueous solvents.
yield
(%)
ee
(%)
time
(days)
entry
14
catalyst
solvent
1
a
b
b
b
Pro-2-Pro
16c
Pro-2-Pro
Pro-2-Pro
CHCl3
MeCNd
CHCl3
THF/H2O
10:1
95
82
88
49
83
95
92
92
5
4
1
1
2b
3
Experimental Section
4
Representative Procedures for Aldol Reactions. a. Water-
Free Conditions. Portions of 0.01-0.04 mmol (5-20% catalyst)
of the selected catalyst were added to 0.2 mmol of aldehyde and
dissolved under N2 atmosphere in 2 mL of dry acetone or CHCl3/
acetone mixture in a 10 mL vial. The reaction was stirred for the
time indicated; subsequently, the solvent was evaporated and 5 mL
of EtOAc and 2 mL of water were added to the crude material.
5
6
b
b
Pro-Pro-1
Pro-1-Pro
CHCl3
CHCl3
10
11
38
37
1
1
a All reactions were run at room temperature with 10 mol % of catalyst
unless otherwise noted. b Taken from reference 17a. c With 20 mol %.
d Reaction run at 82 °C.
(16) Davies, S. G.; Sheppard, R. L.; Smith, A. D.; Thomson, J. E. Chem.
Commun. 2005, 3802.
(17) (a) Kriis, K.; Kanger, T.; Laars, M.; Kailas, T.; Muurisepp, A.-M.;
Pehk, T.; Lopp, M. Synlett 2006, 1699. (b) Kanger, T.; Kriis, K.; Laars,
M.; Kailas, T.; Mueuerisepp, A.-M.; Pehk, T.; Lopp, M. J. Org. Chem.
2007, 72, 5168.
(18) Zhong, G.; Hoffmann, T.; Lerner, R. A.; Danishefsky, S.; Barbas,
C. F., III J. Am. Chem. Soc. 1997, 119, 8131.
(19) Kessler, H.; Schmitt, W. In Encyclopedia of Nuclear Magnetic
Resonance; Grant, D. M., Harris, R. K., Eds.; John Wiley & Sons: New
York, 1996; pp 3527.
Finally, we also tested our catalysts for intramolecular aldol
reactions of 14 (Table 4). While there is little need for
improvement on the cyclization of 14a, which proceeds with
only 3 mol % of proline with 93% ee,1a 14b has proved to be
a more challenging substrate for small molecules serving as
organocatalysts. Proline or other R-amino acids are less ef-
ficient,15 but notably the â-amino acid cis-pentacin furnished
15b in 86% ee.16 Recently, the bismorpholine 16 was discov-
ered, which allows the synthesis of 15b in up to 95% ee,17
(20) (a) Dorman, D. E.; Bovey, F. A. J. Org. Chem. 1973, 38, 2379. (b)
Gratewohl, C.; Wu¨thrich, K. Biopolymers 1976, 15, 2025. (c) Deber, C.
M.; Madison, V.; Blout, E. R. Acc. Chem. Res. 1976, 9, 106.
(21) Fischer, G. Chem. Soc. ReV. 2000, 29, 119.
(15) (a) Shigehisa, H.; Mizutani, T.; Tosaki, S.-Y.; Ohshima, T.;
Shibasaki, M. Tetrahedron 2005, 61, 5057. (b) Bui, T.; Barbas, C. F., III
Tetrahedron Lett. 2000, 41, 6951.
(22) http://www.wavefun.com.
3264 J. Org. Chem., Vol. 73, No. 8, 2008

The organic phases were extracted again with 1 mL of water, dried
(Na2SO4), concentrated, and purified on silica (3:1 hexanes/EtOAc)
to yield the desired aldol product.
recovery of the catalyst (90-95%), which could be reused without
any loss in performance.
b. Homogeneous Acetone/Water Mixture. p-Nitrobenzaldehyde
(38 mg, 0.25 mmol) and catalyst (H-Pro-2-Pro-OH) (17.7 mg,
0.05 mmol) were dissolved in 0.75 mL of a 3:1 acetone/water (molar
ratio 1:30:42 aldehyde/acetone/water), and the reaction mixture was
stirred for 6 h at room temperature. Acetone was evaporated under
reduced pressure, and EtOAc (5 mL) and water (2 mL) were added
to the resulting suspension. The organic layers were separated,
extracted with water (1 mL), dried (Na2SO4), and evaporated. The
residue was purified on silica (3:1 hexanes/EtOAc) to yield 11a
(50 mg, 95% yield, 71% ee).
Acknowledgment. This work was supported by the Deutsche
Forschungsgemeinschaft (SPP 1179 Organokatalyse), the DAAD
(fellowship for V.D’E.), the Fonds der Chemischen Industrie,
and through generous chemical gifts by Degussa Rexim,
Degussa AG.
Supporting Information Available: Experimental procedures
and spectral data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
Catalyst Recovery. The combined aqueous layers were extracted
with Et2O (2 mL) and frozen at -20 °C. Lyophilization allowed
JO800168H
J. Org. Chem, Vol. 73, No. 8, 2008 3265