Asymmetric aldol reaction organocatalyzed by (S)-proline-containing dipeptides: Improved stereoinduction under solvent-free conditions

Article abstract of DOI:10.1021/jo1022469

The organocatalytic activity of the methyl ester of (S)-proline-(S)- phenylalanine, (S,S)-2, in the asymmetric aldol reaction between cyclohexanone and acetone with various aromatic aldehydes under solvent-free conditions in a ball mill has been evaluated. α,α-Dipeptide (S,S)-2 catalyzed the stereoselective formation of the expected aldol products, with higher diastereo-and enantioselectivity relative to similar reactions in solution, up to 91:9 anti:syn diastereomeric ratio and up to 95% enantiomeric excess.(Figure Presented)

Full text of DOI:10.1021/jo1022469

pubs.acs.org/joc
Asymmetric Aldol Reaction Organocatalyzed by
(S)-Proline-Containing Dipeptides: Improved
Stereoinduction under Solvent-Free Conditions
ꢀ
Jose G. Hernandez and Eusebio Juaristi*
ꢀ
´
Departamento de Quımica, Centro de Investigacion y de
Estudios Avanzados del Instituto Politecnico Nacional,
ꢀ
FIGURE 1. Structure of dipeptides (S,S)-1 and (S,S)-2.
ꢀ
Apartado Postal 14-740, 07000 Meꢀxico, D.F., Meꢀxico
organic catalysts that might act as efficient organocatalysts.3
Remarkable examples are (S)-proline-containing R-dipep-
tides4a-e and R-tripeptides,4f-h which have been shown to
retain the catalytic properties of (S)-proline. In particular,
dipeptide (S)-proline-(S)-phenylalanine [(S,S)-1, Figure 1]
has been used to catalyze the enantioselective reaction of
4-nitrobenzaldehyde with acetone, using a DMSO-NMM-
PEMG 5000 system; the aldol product was obtained in high
yield and 73% ee.4b Furthermore, Li and co-workers re-
ported the use of dipeptide (S,S)-1 in the aldol reaction of
4-pyridinecarbaldehyde with cyclohexanone in water,4a and
the anti-β-hydroxy carbonyl product was obtained in good
yield and 73% ee. On the other hand, Sung et al. performed
the enantioselective direct aldol reaction of cyclohexanone
with 4-nitrobenzaldehyde and studied the effect of solvents,
additives, and temperature.
ejuarist@cinvestav.mx
Received November 10, 2010
The major anti diastereomeric product was obtained with
91% ee by using 30 mol % of catalyst (S,S)-1.4c In this
context, Lei and co-workers examined dipeptide (S,S)-1 in
the asymmetric aldol reaction of 4-nitrobenzaldehyde with
cyclohexanone in solid phase media (Al2O3), using 1,4-
diazabicyclo[2.2.2]octane as additive, observing moderate
yield and good diastereo- and enantioselectivity (anti-aldol,
86% ee). Nevertheless, this protocol required long reaction
times (10-180 h).4d
The organocatalytic activity of the methyl ester of (S)-
proline-(S)-phenylalanine, (S,S)-2, in the asymmetric
aldol reaction between cyclohexanone and acetone with
various aromatic aldehydes under solvent-free conditions
in a ball mill has been evaluated. R,R-Dipeptide (S,S)-2
catalyzed the stereoselective formation of the expected
aldol products, with higher diastereo- and enantioselec-
tivity relative to similar reactions in solution, up to 91:9
anti:syn diastereomeric ratio and up to 95% enantiomeric
excess.
With the exception of the work reported by Lei et al.,4d the
above reactions were carried out with an organic solvent as a
reaction medium. As part of our current interest in High
Speed Ball-Milling (HSBM),5 a sustainable mechanochem-
ical technique, we decided to prepare the methyl ester of (S)-
proline-(S)-phenylalanine [(S,S)-2, Figure 1] and evaluate its
organocatalytic activity under solvent-free, “green” reac-
tions conditions. There exists the precedent that (S)-proline
(10 mol %) catalyzes the aldol reaction between acetone and
4-nitrobenzaldehyde under solvent-free conditions in a ball
mill. This reaction required 19 h to take place, and an enantio-
selectivity of 56% ee was reported (entry 1 in Table 1).6a
The aldol reaction is one of the most powerful strategies in
synthetic organic chemistry, since it allows for the formation
of new C-C bonds, that is, facilitates the construction of
larger molecules from smaller ones. The development of
enantioselective versions of the aldol reaction was based for
a long time on the use of preformed enolates, which added to
prochiral carbonyl substrates with activation by metal-based
chiral catalysts.1 Nevertheless, the ability of (S)-proline to
act as an organic catalyst in intramolecular asymmetric aldol
reactions2 has recently motivated the search of other chiral
(4) (a) Lei, M.; Shi, L.; Li., G.; Chen, S.; Fang, W.; Ge, Z.; Cheng, T.; Li,
R. Tetrahedron 2007, 63, 7892–7898. (b) Shi, L.-X.; Qi, S.; Ge, Z.-M.; Zhu,
Y.-Q.; Cheng, T.-M.; Li, R.-T. Synlett 2004, 2215–2217. (c) Chen, Y.-H.;
Sung, P.-H.; Sung, K. Amino Acids 2010, 38, 839–845. (d) Lei, M.; Xia, S.;
Wang, J.; Ge, Z.; Cheng, T.; Li, R. Chirality 2010, 22, 580–586. (e) List, B.;
Martin, H. J. Synlett 2003, 1901–1902. (f) Krattiger, P.; Kovasy, R.; Revell,
J. D.; Ivan, S.; Wennemers, H. Org. Lett. 2005, 7, 1101–1103. (g) Revell, J. D.;
Wennemers, H. Tetrahedron 2007, 63, 8420–8424. (h) Revell, J. D.; Wenne-
mers, H. Adv. Synth. Catal. 2008, 350, 1046–1052.
(1) Mahrwald, R., Ed. Modern Aldol Additions; Wiley-VCH: Weinheim,
Germany, 2004.
(2) (a) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. 1971, 10,
496–497. (b) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615–1621.
(3) See, for example: (a) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.;
Yamamoto, H. Angew. Chem., Int. Ed. 2004, 43, 1983–1986. (b) Zou, W.;
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(5) Hernandez, J. G.; Juaristi, E. J. Org. Chem. 2010, 75, 7107–7111.
(6) (a) Rodrıguez, B.; Bruckmann, A.; Bolm, C. Chem.;Eur. J. 2007, 13,
´
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Ibrahem, I.; Dziedzic, P.; Sunden, H.; Cordova, A. Chem. Commun. 2005,
4946–4948. (c) Alza, E.; Cambeiro, X. C.; Jimeno, C.; Pericas, M. A. Org.
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Lett. 2007, 9, 3717–3720. (d) Almas-i, D.; Alonso, D. A.; Najera, C. Adv.
Synth. Catal. 2008, 350, 2467–2472.
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4710–4722. (b) 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, 5755–5760. (c) Tang,
Z.; Yang, Z.-H.; Cun, L.-F.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z. Org. Lett.
2004, 6, 2285–2287.
ꢁ
1464 J. Org. Chem. 2011, 76, 1464–1467
Published on Web 01/20/2011
DOI: 10.1021/jo1022469
r
2011 American Chemical Society

ꢀ
Hernandez and Juaristi
JOCNote
TABLE 1. Enantiomeric Excesses and Yields of Aldol Product 5l
Observed in the Aldol Reaction of Acetone with 4-Nitrobenzaldehyde
TABLE 2. Enantioselective Aldol Reaction between Cyclohexanone
and 4-Nitrobenzaldehyde, Catalyzed by Dipeptide (S,S)-2 under Ball-
Milling, Solvent-Free Conditionsa
catalyst
[mol %]
time yield ee (R)
[%]
entry
ref
equiv of 3c
[h]
[%]
entry cat. mol [%] time [h] temp [°C] yield [%]b anti:sync ee [%]d
1
2
3
(S)-proline (10)a 6a
2.0
>27
2.0
19
73
56
28
2 (20)b
2 (7)a
6b
this work
24-48 88
82
1
2
3
4
5
6
7
8
22
22
22
22
15
7
4
4
2
1
4
4
4
4
30
-20
-20
-20
-20
-20
-20
-20
96
99
86
66
90
92
56
46
67:33
80:20
83:17
80:20
78:22
90:10
91:9
33
72
84
92
93
95
90
88
4
69c
aUnder ball-milling conditions. bThe reaction was carried out in neat
acetone with a concentration of 0.5 M of aldehyde. cDetermined by
chiral-phase HPLC.
4
1
80:20
On the other hand, the aldol reaction between acetone
and 4-nitrobenzaldehyde was studied by Gong and
co-workers,6b using the methyl ester of (S,S)-proline-phenyla-
lanine, (S,S)-2 (20 mol %), as catalyst in excess acetone, with a
concentration of 0.5 M of 4-nitrobenzaldehyde. The aldol
adduct was obtained with only 28% ee (entry 2 in Table 1).6b
In further work, Gong, et al. prepared a series of small
peptides and evaluated them as catalysts for the asymmetric
direct aldol reaction of hydroxyacetone with aldehydes in
THF/H2O. It turned out that the best catalysts were peptides
with phenylalanine as lipophilic residue. In particular, di-
peptide (S,S)-2 afforded the expected aldol product, (R)-1,4-
dihydroxy-4-(4-nitrophenyl)butan-2-one, in moderate yield
and with 67% ee.6c
aReaction conditions: ketone 3a (0.22 mmol), aldehyde 4a (0.20
mmol), dipeptide (S,S)-2 (1-22 mol %). bCombined yield of the isolated
diastereomers. Determined by 1H NMR spectroscopic analysis. dDe-
termined by chiral-phase HPLC analysis of the anti isomer.
c
and with 69% ee (entry 3 in Table 1). It can be appreciated
that under solvent-free methodology dipeptide (S,S)-2 showed
superior catalytic activity, both in terms of required reaction
time and enantioselectivity, relative to (S)-proline as orga-
nocatalyst (cf. entries 1 and 3 in Table 1). Furthermore,
dipeptide (S,S)-2 was a more efficient organocatalyst under
HSBM solvent-free conditions relative to traditional solu-
tion conditions (cf. entries 2 and 3 in Table 1).
An examination of the effect the amount of catalyst, the
reaction temperature, the time, and the frequency of milling
on the reaction of cyclohexanone 3a with 4-nitrobenzalde-
hyde 4a (1.1:1 ratio of ketone and aldehyde) in the presence
of catalyst (S,S)-2 was undertaken. Initially, the amount of
catalyst employed was 22 mol % and the reactants were ball
milled at 2760 rpm. After 4 h at 30 °C the aldol product was
obtained in high yield, in a diastereomeric ratio of 2:1 in
favor of the anti-diastereomeric product; however, the ob-
served eeanti was low, 33% ee (entry 1 in Table 2). To increase
the enantioselectivity of the reaction, it was decided to carry
out the reaction at lower temperature. After 4 h at -20 °C the
anti diastereomeric product was obtained with excellent yield
(99%), and high diastereo- (80% ds) and enantioselectivity
(72% ee, entry 2 in Table 2).
We then examined the reaction at shorter reaction times;
this greatly favored the enantioselectivity, 84% ee and
92% ee after 2 and 1 h, respectively, although the isolated
yields were lower (cf. entries 2-4 in Table 2).
In view of the satisfactory results obtained at low tem-
perature, all subsequent tests were conducted at -20 °C, and
now the effect of the amount of the catalyst 2 on the reaction
was examined (cf. entries 5-8 in Table 2). The results reveal
that best results are obtained when using 7 mol % of catalyst,
the anti-product being obtained in 95% ee. Nevertheless, it
is interesting that even with 1 mol % of the catalyst, the
enantiomeric excess of the major anti aldol product is
remarkably high (entry 8 in Table 2).
In view of this precedent, it was considered that dipeptide
(S,S)-2 could indeed act as organocatalyst under solvent-free
conditions, employing equimolar amounts of aldehydes and
ketones under HSBM techniques. Although high speed ball-
milling has been applied in the area of synthetic organic
chemistry to promote several solvent-free reactions,7 only a
few organocatalyzed asymmetric reactions have been ex-
plored under HSBM conditions. Thus, the present work is
attractive in the search of alternatives to the traditional
methodologies in solution phase.
Methyl ester dipeptide (S,S)-2 was prepared by condensa-
tion of Cbz-N-protected (S)-proline with phenylalanine
methyl ester hydrochloride, followed by deprotection with
hydrogen and palladium on carbon, according to the general
method for the preparation of dipeptides.8 Complete spec-
troscopic analysis of (S,S)-2 is presented in the Supporting
Information. We then proceeded to carry out the aldol
reaction of acetone with 4-nitrobenzaldehyde under HSBM
conditions in order to compare dipeptide (S,S)-2 with (S)-
proline as chiral organocatalysts, both under HSBM condi-
tions. We also compared the efficiency of dipeptide (S,S)-2 as
organocatalyst in solvent-free conditions relative to tradi-
tional conditions in solution. The aldol reaction was carried
out at -20 °C for 4 h in a ball mill at 2760 rpm, using 7 mol %
of (S,S)-2. The expected product (R)-4-hydroxy-4-(4-
nitrophenyl)butan-2-one (5l) was obtained in 82% yield
(7) (a) Rodrıguez, B.; Bruckmann, A.; Rantanen, T.; Bolm, C. Adv.
´
We also evaluated the effect of the frequency of milling on
the yield and ee of aldol product 5a. When the reaction was
carried out at higher frequency (3080 rpm) the aldol product
was obtained in similar yield but in lower enantiomeric
Synth. Catal. 2007, 349, 2213–2233. (b) Bruckmann, A.; Krebs, A.; Bolm,
C. Green Chem. 2008, 10, 1131–1141. (c) Walsh, P. J.; Li, H.; Anaya de
Parrodi, C. Chem. Rev. 2007, 107, 2503–2545.
€
+
ꢀ
(8) See, for example: Szollosi, G.; London, G.; Balaspiri, L.; Somlai, C.;
ꢀ
Bartok, M. Chirality 2003, 15, S90–S96.
J. Org. Chem. Vol. 76, No. 5, 2011 1465

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Hernandez and Juaristi
JOCNote
excess (76% ee versus 95% ee), perhaps as a consequence of
increased reactor temperature at higher milling speed.6a
Under the optimum reaction conditions (entry 6 in
Table 2), the application of (S)-proline-(S)-phenylalanine
methyl ester, (S,S)-2, as organocatalyst in the direct asym-
metric aldol reaction between cyclohexanone 3a and cyclo-
pentanone 3b and several benzaldehyde derivatives contain-
ing different acceptor and donor substituents 4a-j was
further examined. The data are summarized in Table 3. The
nitro, chloro, and bromo substituents were chosen as elec-
tron-withdrawing groups, and the methoxy substituent as a
representative electron-donating group. It can be appreciated
in Table 3 that benzaldehydes substituted by electron-with-
drawing groups are converted to the corresponding anti-aldol
products in higher yields and enantioselectivities, the latter in
the 82-95% ee range (cf. entries 1-8 in Table 3). By contrast,
the reaction of less reactive benzaldehyde with cyclohexanone
afforded product 5i in 70% yield and with 65% ee (entry 9 in
Table 3). On the other hand, the aldol reaction of p-anisalde-
hyde with cyclohexanone afforded the aldol adduct 5j in
moderate yield (62%) and enantioselectivity, 57% ee (entry
10 in Table 3). Finally, the reaction of cyclopentanone with
4-nitrobenzaldehyde generated the syn aldol in major propor-
tion with very low enantioselectivity, 3% ee, while the anti
product 5k was obtained with 55% ee (entry 11 in Table 3).
As proposed for other cases where catalysis by dipeptides3a,9
and prolinamides is operative,10 it is likely that dipeptide (S,S)-
2 catalyzes the aldol reaction via the transition state depicted in
Figure 2. It is suggested that a hydrogen bond between amide
group and the aldehyde is the essential controlling interaction.
In solution, this interaction is apparently weakened by solva-
tion and therefore enantioinduction is less effective.
TABLE 3. Scope of Direct Asymmetric Aldol Reaction of Cyclic Ketones
(3a,b) with Various Aldehydes Catalyzed by Dipeptide (S,S)-2 under Ball-
Milling Conditionsa
By contrast, under solvent free conditions there is no
competition between the aldehyde and the solvent or addi-
tives for hydrogen bond formation and this interaction is
maximized. On other hand, it has been reported that the
stereoselectivity of aldol reactions carried out in, on, or in the
presence of water can be improved by using catalyst with
hydrophobic regions. Examples of such organocatalysts are
tryptophan,11 phenylalanine,11 and short peptides such as
Pro-(Phe)3-OMe6c or NOBIN-prolinamide.12
In the case of tryptophan and NOBIN-prolinamide the
authors propose the formation of a hydrophobic core that
facilitates noncovalent π-π interactions between aromatic
rings of the catalyst and the substrate, which are probably
responsible for the high estereoselectivity in aldol product
formation. This interaction may also be relevant in the
transition state for the aldol reaction of interest in the present
work. Indeed, the absence of solvent reduces molecular
motion and π-stacking interactions should be more effec-
tive13 (Figure 2).
aReaction conditions: ketone 3 (0.22 mmol), aldehyde 4 (0.20 mmol).
bCombined yield of the isolated diastereomers. cDetermined by 1H
NMR spectroscopic analysis. dDetermined by chiral HPLC analysis of
the anti isomer.
ꢀ
(9) Dziedzic, P.; Zou, W.; Hafren, J.; Cordova, A. Org. Biomol. Chem.
ꢀ
2006, 4, 38–40.
(10) Fuentes de Arriba, A. L.; Simon, L.; Raposo, C.; Alcazar, V.; Sanz,
In summary, we have demostrated that dipeptide (S,S)-2 is
a more efficient organocatalyst in the asymmetric aldol
reaction under solvent-free conditions, relative to reaction
in solution. This is a significant result and suggests that non-
covalent interactions which are enhanced in the absence of
solvents are crucial for the course of the reaction. In parti-
cular, it is shown that ball milling activates the aldol reaction
between cyclohexanone and various aromatic aldehydes.
The reaction proceeds efficiently affording the anti aldol
ꢀ
ꢀ
~
ꢀ
F.; Muniz, M. F.; Moran, J. R. Org. Biomol. Chem. 2010, 8, 2979–2985.
(11) Jiang, Z.; Liang, Z.; Wu, X.; Lu, Y. Chem. Commun. 2006, 2801–
2803.
(12) Wang, C.; Jiang, Y.; Zhang, X.-X.; Huang, Y.; Li, B.-G.; Zhang, G.-
L. Tetrahedron Lett. 2007, 48, 4281–4285.
(13) For discussions on hydrophobic interactions and π-stacking, see for
example: (a) Otto, S.; Engberts, J. B. F. N. Org. Biomol. Chem. 2003, 1, 2809–
2820. (b) Gruttadauria, M.; Giacalone, F.; Noto, R. Adv. Synth. Catal. 2009,
351, 33–57. (c) Jones, B. G.; Chapman, B. J. Synthesis 1995, 475–497. (d)
Saha, S.; Moorthy, J. N. Tetrahedron Lett. 2010, 51, 912–916.
1466 J. Org. Chem. Vol. 76, No. 5, 2011

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Hernandez and Juaristi
JOCNote
Experimental Section
General Procedure for the Intermolecular Aldol Reaction
Catalyzed by (S,S)-2, in a Ball Mill. A mixture of the catalyst
(S,S)-2 (7 mol %), cyclohexanone (20.56 mg, 0.22 mmol),
and 4-nitrobenzaldehyde (30.2 mg, 0.2 mmol) was vigorously
milled for 4 h at 2760 rpm at -20 °C in a digital Mixer/
Amalgamator used with a reactor made of Nylamid (cylinder,
25 mm long and with a diameter of 10 mm) containing one
stainless steel ball with a 5 mm diameter. Then the mixture
was dissolved in AcOEt and extracted. The organic phase was
dried over MgSO4, then concentrated to give the crude reac-
tion mixture that was purified by flash chromatography (silica
gel, hexane/EtOAc: 10:1-3:1) to afford aldol mixture (syn-
anti). The ee values were determined by HPLC on a chiral
column.
FIGURE 2. Proposed transition state model of the aldol reaction
catalyzed by (S,S)-2.
products with good diastereo- and enantioselectivities. In
addition, aldol products 5a, 5d, 5i, and 5l were obtained in
shorter reaction times and with higher stereoselectivity by
using 7 mol % of dipeptide (S,S)-2 relative to conditions
employing 10% mol of amino acid (S)-proline, also in a ball
mill under solvent-free conditions.6a,14
Research toward the examination of other dipeptides with
potential organocatalytic activity in asymmetric, organoca-
talyzed reactions is already in progress in our laboratory.
Acknowledgment. The authors are indebted to Conacyt,
ꢀ
Mexico for financial support via grant 60366-Q. J.G.H. thanks
ꢀ
Conacyt, Mexico for a doctoral fellowship (no. 22211).
Supporting Information Available: Experimental proce-
dures, copies of NMR spectra, and HPLC chromatograms.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(14) The work described herein refers to experiments carried out at the
milligram scale; nevertheless, the performance of catalyst (S,S)-2 should be
preserved at greater scales, e.g. grams scale, when using ball mills of the
proper size. See ref 6a.
J. Org. Chem. Vol. 76, No. 5, 2011 1467