Heterogeneous catalysis of the asymmetric aldol reaction by solid-supported proline-terminated peptides

Article abstract of DOI:10.1016/j.tetasy.2005.06.031

Peptides with prolyl N-termini, attached to a PEG-polystyrene (TG) synthesis resin, have been tested as heterogeneous catalysts for the aldol reaction between acetone and p-nitrobenzaldehyde. Proline directly attached to TG showed good activity but poor e

Full text of DOI:10.1016/j.tetasy.2005.06.031

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2487–2492
Heterogeneous catalysis of the asymmetric aldol reaction by
solid-supported proline-terminated peptides
Marc R. M. Andreae and Anthony P. Davis*
School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, UK
Received 31 May 2005; accepted 22 June 2005
Abstract—Peptides with prolyl N-termini, attached to a PEG–polystyrene (TG) synthesis resin, have been tested as heterogeneous
catalysts for the aldol reaction between acetone and p-nitrobenzaldehyde. Proline directly attached to TG showed good activity but
poor enantioselectivity. However, in combination with serine or threonine, the selectivity improved considerably. At ꢀ25 ꢀC, the
dipeptide H-Pro-Ser-NH-TG achieved 82% ee. The H-Pro-Ser/Thr dipeptides may be seen as self-contained Ôcatalytic head-groupsÕ
for the development of more sophisticated aldol organocatalysts.
ꢁ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
the acceptor is the carbonyl oxygen. The carboxyl can be
replaced by other groups as in pyrrolidines 3,4e,8 49 and
5.4b,10 However in simple amides such as 64b it seems
that the CONH is insufficiently acidic, and these mole-
cules are therefore less effective.
Organocatalysis via enamine intermediates has proven
to be an effective strategy in asymmetric synthesis.1
The proline-catalysed intramolecular aldol reaction
(the Hajos–Parrish–Eder–Sauer–Wiechert reaction)
stood for many years as an elegant, classical example
of enantioselective catalysis.2 Recently, the scope was
extended through the discovery of an intermolecular
version, by List et al.,3 and since then the field has devel-
oped at pace. Proline 1, and other chiral pyrrolidines,
have been used for the enantioselective catalysis of a
wide range of aldol reactions4 as well as Mannich reac-
tions,5 conjugate additions6 and a variety of oxidative
transformations.7 The reactions proceeded via enamine
intermediates, as in Scheme 1 for the proline-catalysed
aldol addition. An important feature in most cases is a
hydrogen bond between an acidic proton in the catalyst
and an acceptor atom in the substrate. In transition state
2, the H-bond donor is the proline carboxyl unit, while
This requirement for an acidic proton places two limita-
tions on the development of proline-based catalysts.
Firstly, it is useful to immobilise catalysts on insoluble
polymers, so that they can be easily recovered.11 How-
ever, if proline is attached to a resin via its carboxyl
group, the ester or amide linkage will not promote enan-
tioselective catalysis.12 Secondly, there is potential for
creating more complex catalysts, perhaps with enzyme-
like features, by using proline to acylate larger architec-
tures (e.g., peptides). Again, immobilisation is useful as
it allows the preparation and screening of large libraries
of catalysts, for example, of form 7.13 Unfortunately,
most such structures will lack acidic protons and should
therefore be less active than proline itself.14
N
O
O
N
H
N
N
H
N
H
N
H
N
H
N N
N
NH2
SO2Ar
H
H
3
4
5
6
*
Corresponding author. Tel.: +44 117 924 6334; fax: +44 117 929 8611; e-mail: Anthony.Davis@bristol.ac.uk
0957-4166/$ - see front matter ꢁ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.06.031

2488
M. R. M. Andreae, A. P. Davis / Tetrahedron: Asymmetry 16 (2005) 2487–2492
‡
O
N
H
1
OH
N
H
O
O
R
+
O
R'
O
O
R
R'
2
R
R'
R
N
OH
O
OH R'
O
O
Scheme 1.
O
N
variable segment
R1
H
N
resin support
O
H
H
NH
NH
R2
O
7
8
O
N
O
R
O
H
N
H
N
O
N
N
R'
O
H
H
H
H
R1
R
O
R2
9
10 R = H, Me
In the context of our work on combinatorial cataly-
sis,13f–h we sought to address these problems.
Specifically, we required a self-contained catalytic unit,
which could transform a polymer-bound amino-deriva-
tised scaffold into a Ôsynthetic aldolaseÕ. Prolinamide, as
in 7, seemed unpromising as discussed above. However,
Gong and Wu et al. had found that hydroxyprolin-
amides of general form 8 show good activity and enantio-
selectivity.15 Presumably the hydroxy group forms a
second hydrogen bond to the carbonyl oxygen in
the aldol transition state 9, reinforcing the effect of
the NH and restoring activity. The polymer-bound
Pro-Ser/Thr dipeptides 10 conform to 8 and we
therefore decided to test these units for catalytic activ-
ity. We herein report that they are indeed effective
enantioselective catalysts for the direct aldol. The
results confirm the potential of these combinations as
general Ôcatalytic head-groupsÕ, and demonstrate a
practical method for performing enantioselective aldol
additions with heterogeneous polymer-bound organo-
catalysts.
2. Results and discussion
Peptides were synthesised on Novasyn TG amino resin,
an amine-terminated PEG–polystyrene graft copolymer
chosen for its compatibility with a wide range of
solvents.16 Standard Fmoc-based methodology was
employed, using HBTU, HOBt and DIPEA as coupling
reagents. Between each coupling step any remaining free
amino functions were capped with acetic acid anhydride
before Fmoc deprotection of the terminal amino acid.
The side-chain protection was removed with 5% TFA
in dichloromethane.
The sequences listed in Table 1 were synthesised and
tested as catalysts for the addition of acetone (used as
solvent) to p-nitrobenzaldehyde 11, to give hydroxy-
ketone 12 (Scheme 2). Reactions were allowed to run
for 24 h at room temperature (20 ꢀC) in the presence of
13 mol % of resin-bound catalyst. Control experiments
established that no conversion took place in the absence
of the catalyst, or in the presence of N-acetylated resin.

M. R. M. Andreae, A. P. Davis / Tetrahedron: Asymmetry 16 (2005) 2487–2492
2489
Table 1. Catalysis of the direct aldol reaction between 11 and acetone by resin-bound peptidesa
Entry
Catalyst
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
H-Pro-NH-TG
93
78
94
87
30
22
63
68
60
61
51
77
76
75
H-Pro-Ala-NH-TG
H-Pro-Ser-NH-TG
H-Pro-D-Ser-NH-TG
H-Pro-Thr-NH-TG
H-Pro-D-Thr-NH-TG
H-Pro-Cys-NH-TG
H-Pro-Ser-Phe-NH-TG
H-Pro-Ser-Trp-NH-TG
H-Pro-Ser-Tyr-NH-TG
Quantitative
87
89
22
13
29
10
a For conditions and general catalyst structure, see Scheme 2.
b Determined by HPLC, with internal standard.
c Determined by HPLC on Chiralpak-AS-H. The R product 12 was preferred in each case.
Novasyn TG resin
[AA2]
NH
O
N
H
HN
[AA1]
OH
O
13 mol %
AA1,2 = amino acids
O
O2N
O2N
O
(solvent), 20oC, 24 h
12
11
Scheme 2.
The results of the trials (yields and enantioselectivities)
are summarised in Table 1. An initial experiment
employing resin-bound L-proline revealed, unexpectedly
that activity was quite high (entry 1).17 However, the
enantioselectivity was poor. A number of dipeptides
were then tested (entries 2–7). The Pro-Ala combination
behaved similarly to that of proline but, as hoped, the
dipeptides incorporating serine or threonine were more
successful. The enantiomeric excesses, at 60–70%, were
in the range achieved by soluble hydroxyprolinamides
8 for the same reaction under similar conditions.15 Dif-
ferences between the four combinations were small, but
Pro-D-Ser gave slightly higher selectivity. Yields were
good throughout. Pro-Cys was appreciably less selec-
tive, but still an improvement over Pro-Ala.
temperatures and reaction times. It was therefore of
interest to test a TG-bound catalyst under a range of
conditions, firstly to maximise selectivity and secondly
to explore its compatibility with different media. The
addition of acetone to 11, catalysed by H-Pro-Ser-
NH-TG, was investigated in a number of solvents and
at several temperatures. The results are summarised in
Table 2. Entry 1 is notable, in that it confirms that
the catalyst can operate in aqueous conditions.18 Cata-
lysis seems to be very efficient, although the selectivity
is low. Performance in DMSO/acetone was acceptable,
but DMF and CH2Cl2 were unsuitable as co-solvents.
Entries 5 and 6 show that the polymer-bound catalyst
may be used at reduced temperatures, and that this
improves enantioselectivity. At ꢀ25 ꢀC, an enantiomeric
excess of 82% was achieved. However, a further
decrease in temperature to ꢀ45 ꢀC proved unproductive
(entry 7).
As a first move towards more complex catalysts, three
tripeptides were also tested (entries 8–10). Modelling
suggested that an aromatic side chain in AA2 (Scheme
2) could make favourable p–p contacts with aromatic
aldehyde substrates, so variants incorporating phenyl-
alanine, tryptophan and tyrosine were explored. In the
event, selectivities were increased slightly but yields were
lowered. The tripeptides may fold in such a way as to
reduce activity, perhaps by restricting access to the proline
nitrogen. Though disappointing, the results illustrate the
potential of Pro-Ser, etc. as catalytic head-groups in
wider-ranging studies.
Finally, to investigate the role of the polymer support,
the Pro-Ser dipeptide was synthesised on aminomethyl
polystyrene (PS) resin. The product H-Pro-Ser-NH-PS
was tested as catalyst for the aldol, following the meth-
od shown in Scheme 2 and Table 1. Product 12 was
formed in 60% enantiomeric excess, but only in 26%
yield. Thus a change from TG to PS had little effect
on the enantioselectivity, but did substantially lower
the reaction rate. The reason for the reduced activity
is unclear at present, but may be connected with the
apolar, hydrophobic environment provided by the
PS.19
To extract the optimum performance from a catalyst it
is necessary to optimise procedures, by varying solvents,

2490
M. R. M. Andreae, A. P. Davis / Tetrahedron: Asymmetry 16 (2005) 2487–2492
Table 2. Catalysis of 11 + acetone ! 12 by H-Pro-Ser-NH-TG
Entry
Solvent
Temperature (ꢀC)
Time (h)
Conversion (%)
ee (%)
1
2
3
4
5
6
7
Acetone/water (1:1)
DMSO/acetone (4:1)
DMF/acetone (4:1)
CH2Cl2/acetone (4:1)
Acetone
20
20
20
16
16
16
16
72
41
48
Quantitative
22
59
39
n.d.a
71
70
<10
<4
>98
>98
35
20
ꢀ15
ꢀ25
ꢀ45
Acetone
Acetone
82
68
Effects of temperature and solvent.
a Not determined.
3. Conclusion
time of 3 min, the activated amino acids were added to
the pre-swollen resin in N,N-dimethylformamide (1 ml)
and agitated overnight. The resin was then filtered,
washed with N,N-dimethylformamide (3 · 10 ml), meth-
anol (3 · 10 ml) and dichloromethane (3 · 10 ml) and
dried under high vacuum. The extent of coupling was
monitored visually by the use of the NF31 test.21 If
the test revealed unreacted NH2 groups (beads stained
red), the reaction was repeated. Before the coupling of
a new amino acid, the beads were treated with pyridine
and acetic acid anhydride in dry dichloromethane to cap
the remaining free amino functions. Typically, the resin
was suspended in dry DCM (2.8 ml), at which point pyr-
idine (0.17 ml, 2.18 mmol) and acetic anhydride
(0.17 ml, 1.80 mmol) were added, and the mixture agi-
tated overnight. After removal of the solution, the beads
were washed with DMF (3 · 10 ml), methanol
(3 · 10 ml) and DCM (3 · 10 ml). The 9-fluorenylmeth-
oxycarbonyl protecting group was removed after each
cycle by shaking with 20% piperidine in N,N-dimethyl-
formamide. Typically the resin was treated with piper-
idine in N,N-dimethylformamide (20%, 2 ml), agitated
for 30 min and isolated by filtration. This process was
repeated twice, agitating for 30 min in the first case
and 2 h in the second. After removal of the solution
the beads were washed with DMF (3 · 10 ml), methanol
(3 · 10 ml) and DCM (3 · 10 ml). The acid labile pro-
tecting groups were deprotected after the addition of
the last amino acid by treatment of the beads with 5%
trifluoroacetic acid in dichloromethane containing 5%
of triisopropylsilane for 1.5 h. Typically the resin was
treated with a solution of TFA (5 vol %) and triisoprop-
ylsilane (5 vol %) in dry DCM (2 ml), agitated for
30 min and isolated by filtration. This process was
repeated twice, agitating for 30 min in the first case
and 3 h in the second. After removal of the solution
the beads were washed with DMF (3 · 10 ml), methanol
(3 · 10 ml) and DCM (3 · 10 ml).
In conclusion, we have shown that peptides with Pro-
Ser/Thr N-termini, bound to a PEG–polystyrene insolu-
ble polymer, can act as heterogeneous enantioselective
catalysts for the aldol addition. Catalyst loadings, yields
and enantioselectivities are comparable to those for sol-
uble analogues.15 This research points the way towards
the development of more sophisticated aldol catalysts
through solid phase parallel synthesis and on-bead
screening.
4. Experimental
4.1. General
Synthesis resins were bought from Nova Biochem. UV/
vis spectra were recorded on a Thermo Helios c spectro-
meter and processed with Vision Pro 1.0 software. Ana-
lytical HPLC was performed using an Anachem Gilson
Model 156 with Unipoint Version 3.01 software. All
conversions were estimated by the comparison of the
product peak areas to the sum of all peak areas.
(4R,4S)-Hydroxy-4-(40-nitrophenyl)butan-2-one rac-12
was prepared according to a literature procedure.20
Solid phase peptide synthesis was performed in plastic
syringes with agitation on a blood tube rotator. The
amino acids used were all Fmoc protected. The amino
acids Ser, Cys and Thr carried trityl side-chain protec-
tion, Tyr was O–t-Bu protected.
4.2. Solid phase peptide synthesis general protocol
All peptides were synthesised manually using Nova Syn
TG aminoꢀ1resin (HL, 110 lm beads, loading =
0.45 mmol g
or LL, 130 lm beads, loading =
0.29 mmol gꢀ1) or aminomethyl polystyrene resin HL
(loading = 1.3 mmol gꢀ1). Three equivalents of N-a-9-
fluorenylmethoxycarbonyl amino acids were used in
each coupling step. The amino acids were activated in
N,N,-dimethylformamide by the addition of two
coupling solutions. Coupling solution 1 was prepared
by dissolving N-[(1H-benzotriazolo-1-yl)(dimethyl-
amino)methylene]-N-methylmethanaminium tetrafluo-
4.3. Preparation of N-acetylated TG resin
Nova Syn TG amino resin (HL, 110 lm beads, load-
ing = 0.45 mmol gꢀ1, 100 mg) was suspended in 2.8 ml
dry dichloromethane and acetic anhydride (170 ll,
1.80 mmol) and pyridine (170 ll, 2.18 mmol) then
added. The mixture was agitated overnight. The resin
was then filtered, washed with DMF (3 · 10 ml), metha-
nol (3 · 10 ml) and DCM (3 · 10 ml) and dried under
high vacuum.
roborate
N-oxide
(HBTU)
(3.00 equiv)
and
1-hydroxybenzotriazole (HOBT) (3.00 equiv) in
N,N-dimethylformamide (0.5 ml). The second solution
consisted of diisopropylethyl amine (3.00 equiv) in
N,N-dimethylformamide (0.5 ml). After an activation

M. R. M. Andreae, A. P. Davis / Tetrahedron: Asymmetry 16 (2005) 2487–2492
Table 3. Loadings determined for polymer bound peptide catalysts
2491
2 ml vial, a portion of this solution (120 ll 7.60 mg 4-
nitrobenzaldehyde 11, 0.05 mmol) was mixed with
27 mg (13 mol %) of H-Pro-Ser-NH-TG and an appro-
priate volume of co-solvent to give the media listed in
Table 2 (entries 1–4). The mixture was agitated at room
temperature using a blood tube rotator for 24 h.
Samples were withdrawn and analysed by HPLC as
described above.
Peptide
Loading (mmol gꢀ1
)
TG-Ser-Pro
TG-D-Ser-Pro
TG-Thr-Pro
TG-D-Thr-Pro
TG-Ala-Pro
TG-Cys-Pro
0.24
0.25
0.30
0.28
0.20
0.25
0.17
0.35
0.34
0.43
0.36
TG-Pro
TG-Phe-Ser-Pro
TG-Phe-D-Ser-Pro
TG-Trp-Ser-Pro
TG-Tyr-Ser-Pro
Acknowledgements
This research was supported by the EPSRC (GR/
R42757/01).
4.4. Estimation of peptide loading
References
The loading of the peptides on the resin was determined
by UV spectroscopy of the soluble by-product from the
final Fmoc deprotection step. 9-Fluorenylmethoxycar-
bonyl-amino acid resin (ꢁ3 mg, weighed accurately)
was placed in a 5 ml sample tube and freshly prepared
20% piperidine in N,N,-dimethylformamide added. The
resin was agitated for 20–30 min. Three millilitres of
the solution was transferred into a UV cell and the
absorbance at 290 nm was read. The loading on the
resin in mmol gꢀ1 was obtained from the expression
(Abssample ꢀ Absref)/(1.65 · mg of resin).22 Results are
given in Table 3.
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4.5. General procedure for aldol reactions between
4-nitrobenzaldehyde 11 and acetone (no added solvent)
In a 2 ml vial, 4-nitrobenzaldehyde 11 (7.60 mg,
0.05 mmol) and polymer-supported catalyst (13 mol %)
were mixed with 600 ll of acetone (470 mg, 8.2 mmol,
160 equiv). For experiments at room temperature, the
mixture was agitated using a blood tube rotator. For
reactions at reduced temperature, the vials were sus-
pended in a cold bath and the mixture stirred with a
magnetic follower. At the end of the experiment,
samples (30 ll) were withdrawn and diluted with 1 ml
isopropanol/n-hexane (1:9). Conversions and enantio-
meric excesses were determined by HPLC [Daicel
Chiralpak-AS-H, isopropanol/n-hexane (1:9), 1.3 ml/
min]. Quantification was performed using naphthalene
as the internal standard. Retention times (tR, min):
4-nitrobenzaldehyde 11, 22.0; (R)-4-hydroxy-4-(4-nitro-
phenyl)butan-2-one 12, 25.3; (S)-4-hydroxy-4-(4-nitro-
phenyl) butan-2-one ent-12, 32.3. In some cases, the
by-product (E)-4(40-nitrophenyl)-2-oxo-3-butene was
detected at tR = 37.5. Assignment of the absolute config-
uration was made by comparison with the literature
data.15 Each experiment was repeated, giving self-
consistent yields and enantiomeric excesses.
4.6. General procedure for aldol reactions between
4-nitrobenzaldehyde 11 and acetone, catalysed by
H-Pro-Ser-NH-TG, in the presence of co-solvents
8. Hartikka, A.; Arvidsson, P. I. Tetrahedron: Asymmetry
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9. Berkessel, A.; Koch, B.; Lex, J. Adv. Synth. Catal. 2004,
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A stock solution of 4-nitrobenzaldehyde 11 (63 mg,
0.42 mmol) in acetone (1.00 ml) was prepared. In a
10. Nakadai, M.; Saito, S.; Yamamoto, H. Tetrahedron 2002,
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M. R. M. Andreae, A. P. Davis / Tetrahedron: Asymmetry 16 (2005) 2487–2492
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Org. Lett. 2005, 7, 1101In most cases the peptides
possessed free carboxyl termini, and therefore required
testing in solution. An elegant exception featuring
on-bead screening was, published during the preparation
of this manuscript.14e
12. As an alternative, 4-hydroxyproline can be attached to a
polymer via the 4-OH, leaving the amine and carboxyl
units free to participate in catalysis. Thus far, this
approach has been restricted to soluble PEG-based
polymers. See: Benaglia, M.; Celentano, G.; Cozzi, F.
Adv. Synth. Catal. 2001, 343, 171; Benaglia, M.; Cinquini,
M.; Cozzi, F.; Puglisi, A.; Celentano, G. Adv. Synth.
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16. White, P.; Dorner, B.; Steinauer, R. Synthesis Notes. In
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17. Good activities, but low enantioselectivities, have been
reported recently for other simple prolinamides. See:
Tang, Z.; Jiang, F.; Cui, X.; Gong, L. Z.; Mi, A. Q.;
Jiang, Y. Z.; Wu, Y. D. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 5755.
13. For on-bead screening of catalyst libraries, see: (a) Taylor,
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43, 4612; (f) De Muynck, H.; Madder, A.; Farcy, N.; De
18. For other organocatalytic aldol reactions in aqueous
media, see Refs. 4e and 14c and Nyberg, A. I.; Usano,
´
A.; Pihko, P. M. Synlett 2004, 1891; Cordova, A.; Notz,
¨
´
´
Clercq, P. J.; Perez-Payan, M. N.; Ohberg, L. M.; Davis,
W.; Barbas, C. F. Chem. Commun. 2002, 3024.
19. For example, water is required for the last step in Scheme
1.
20. Sbokat, K.; Uno, T.; Schultz, P. G. J. Am. Chem. Soc.
1994, 116, 2261.
21. Madder, A.; Farcy, N.; Hosten, N. G. C.; De Muynck, H.;
De Clercq, P. J.; Barry, J.; Davis, A. P. Eur. J. Org. Chem.
1999, 2787.
22. White, P.; Dorner, B.; Steinauer, R. Synthesis Notes. In
Novabiochem 2002/3 Catalogue; CN Biosciences: UK,
2002, p 3.4.
A. P. Angew. Chem., Int. Ed. 2000, 39, 145; (g) Muller, M.;
¨
Mathers, T. W.; Davis, A. P. Angew. Chem., Int. Ed. 2001,
40, 3813; (h) Johansson, K.-J.; Andreae, M. R. M.;
Berkessel, A.; Davis, A. P. Tetrahedron Lett. 2005, 46,
3923.
14. For studies of catalysis by prolyl peptides, see: (a)
Martin, H. J.; List, B. Synlett 2003, 1901; (b) Kofoed,
J.; Nielsen, J.; Reymond, J. L. Bioorg. Med. Chem. Lett.
2003, 13, 2445; (c) Tang, Z.; Yang, Z. H.; Cun, L. F.;
Gong, L. Z.; Mi, A. Q.; Jiang, Y. Z. Org. Lett. 2004, 6,