Proline-β3-amino-ester dipeptides as efficient catalysts for enantioselective direct aldol reaction in aqueous medium

Article abstract of DOI:10.1021/jo902106r

(Chemical Equation Presented) Dipeptides obtained from L-proline and β³-L-amino acids are reported to catalyze enantioselective direct aldol reaction in aqueous medium, leading to significant anti: syn diastereomeric ratios and enantiomeric exc

Full text of DOI:10.1021/jo902106r

pubs.acs.org/joc
naturally occurring amino acids,4-8 due to both their low
Proline-β3-Amino-Ester Dipeptides as Efficient
Catalysts for Enantioselective Direct Aldol Reaction
in Aqueous Medium
cost and availability in highly enantiopure form.
Recently, Singh’s group have reported,9 along the line of
former reports10 by Wu et al., some new L-proline amides
having an extra chiral center at the R position of the amide
nitrogen atom and a polar, bulky group at the β position.
They are highly efficient organocatalysts carrying out dia-
stereo- and enantioselective direct aldol reactions in both
organic and (much better) aqueous medium.
Mauro De Nisco,*,§ Silvana Pedatella,§ Hidayat Ullah,†
†
§
‡
€
€
€
Javid H. Zaidi, Daniele Naviglio, Ozgur Ozdamar, and
Romualdo Caputo§
§Dipartimento di Chimica Organica e Biochimica,
Universitaꢀ di Napoli Federico II, Via Cintia, 4 Napoli 80126,
Italy, †Department of Chemistry, Quaid-i-Azam University,
Such new molecules aroused our attention for their amino
moieties that recall C-2 substituted β3-amino acids, whose
preparation we had reported rather recently11 as a part of our
current interest in the chemistry of β3-L-amino acids. As
a matter of fact, the above-mentioned proline amides can
be regarded as dipeptides of L-proline and C-2 substituted
β3-amino acids, obviously lacking the C-terminal carboxyl
group (whose usefulness, however, will be illustrated fur-
ther on).
‡
Islamabad 45320, Pakistan, and Ondokuz Mayis
€ € €
Universitesi, Fen Edebiyat Faku€ltesi, Kimya Bolumu,
Samsun 55200, Turkey
denisco@unina.it
Received October 5, 2009
In this view, we wanted to investigate the behavior of some
real dipeptides coming from coupling of L-proline with
miscellaneous β3-L-amino acids as catalysts for enatioselec-
tive direct aldol reactions. The dipeptides tested were com-
pounds 1a-f,12 containing simple C-2 unsubstituted β3-
L-amino acids13 and, in addition, compounds 1g and 1h,12
carrying at C-2 a polar (NH2) group11b and a bulky polar14,15
(NHTs) group,11b respectively (Figure 1).
The aldol addition of cyclohexanone and 4-nitrobenzal-
dehyde (Figure 2) was chosen as the test reaction for the
catalytic activity since, from the current literature,9 it ap-
pears to lead to the poorest results in terms of both diastereo-
meric ratios and enantiomeric excesses.
The reactions were carried out in three different, com-
monly used mediums, namely water, brine,3a,16 and THF,
and afforded quite interesting results that are shown in
Tables 1-3.
Dipeptides obtained from L-proline and β3-L-amino acids
are reported to catalyze enantioselective direct aldol
reaction in aqueous medium, leading to significant anti:
syn diastereomeric ratios and enantiomeric excesses. The
simple introduction of a polar substituent at the C-2
position of the β3-L-amino acid was also found to enhance
appreciably both diastereo- and enantioselectivity of the
catalyst.
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Published on Web 11/25/2009
DOI: 10.1021/jo902106r
r
2009 American Chemical Society

De Nisco et al.
JOCNote
TABLE 2. Cyclohexanone/4-Nitrobenzaldehyde-Catalyzed Aldol
Reactions in Brine (25° C, 48 h)
catalyst
mol %
yield [%]a
dr (anti:syn)b
ee [%]c
1a
10
3
10
3
10
3
10
3
10
3
10
3
>99
>99
98
81
>99
99
>99
>99
87
72
96
77:23
80:20
94:6
54
56
88
88
76
67
86
77
89
87
90
89
1b
1c
1d
1e
1f
94:6
89:11
86:14
92:8
90:10
93:7
94:6
FIGURE 1. L-Proline dipeptide catalysts for the enantioselective
aldol reaction.
93:7
93:7
98
aAfter chromatography. bDetermined by 1H NMR. cDetermined by
HPLC on chiral column.
TABLE 3. Cyclohexanone/4-Nitrobenzaldehyde-Catalyzed Aldol
Reactions in THF (25° C, 48 h)
catalyst
mol %
yield [%]a
dr (anti:syn)b
ee [%]c
1a
10
3
10
3
10
3
10
3
10
3
10
3
49
87
70
40
48
48
70
66
90
36
36
38
90:10
91:9
86
85
35
38
44
49
38
48
39
42
43
44
FIGURE 2. Aldol addition of cyclohexanone and 4-nitrobenzal-
dehyde.
1b
1c
1d
1e
1f
87:13
86:14
85:15
85:15
82:18
87:13
86:14
86:14
87:13
84:16
TABLE 1. Cyclohexanone/4-Nitrobenzaldehyde-Catalyzed Aldol
Reactions in Water (25° C, 48 h)
catalyst
mol %
yield [%]a
dr (anti:syn)b
ee [%]c
1a
10
3
10
3
10
3
10
3
10
3
10
3
92
96
72
69
98
89
99
97
81:19
82:18
93:7
92:8
91:9
90:10
94:6
92:8
94:6
93:7
92:8
91:9
45
50
83
78
84
75
87
77
90
85
84
81
1b
1c
1d
1e
1f
aAfter chromatography. bDetermined by 1H NMR. cDetermined by
HPLC on chiral column.
of the recovered catalyst) whereas diastereomeric ratios and
enantiomeric excesses remained substantially at the same
level.
>99
99
78
70
To emphasize the role of a polar substituent β to the
peptide nitrogen atom, we evaluated the effect of both a
substituent like -NH2 and a polar,14,15 cumbersome sub-
stituent, like -NHTs, on the catalytic activity of our less
efficient catalyst, 1a, in aqueous medium.
The new C-2 substituted dipeptides, 1g and 1h, were
synthesized from the already reported11b compound 2, as
shown in Scheme 1. Their activity was tested in both water
and brine at different temperatures (25°, 4°, and, brine only,
-16 °C), using two catalyst loadings (10% and 3%) for each
experiment. All the reactions were duplicated and the aver-
age results are reported in Table 4.
It is worthy of note that the enantiomeric excesses obta-
ined from 1g were in the range 74-90% vs. the range 45-
56% of 1a that has the same skeleton, without the -NH2
group at C-2. The same trend is evident in the anti:syn
diastereomeric ratios that range between 80:20 and 97:3 vs.
the range 77:23 to 82:18 afforded by compound 1a.
Compound 1h was tested under the same experimental
conditions and gave on the whole poorer results in compar-
ison with 1g (Table 4). Only the chemical yields were some-
what higher.
aAfter chromatography. bDetermined by 1H NMR. cDetermined by
HPLC on chiral column.
Such results deserve some comments: it is clear that
dipeptides 1b-f work very well in aqueous medium (water
and brine) rather than in organic solvents (anhydrous THF).
Chemical yields of the catalyzed aldol reactions are satisfac-
torily high3a,6,9,17 and diastereomeric ratios and enantio-
meric excesses are all significant. The best results were
obtained with dipeptides 1e and 1f, bearing the side chains
of tyrosine and tryptophan, respectively. This may be ac-
counted for by the possibility for the aromatic side chains of
these compounds to form in the transition state a hydropho-
bic core with the other hydrophobic substrates in water.3a,6
π-π stacking interactions may also be involved6 in the
transition states of the reactions. Rather oddly, the dipeptide
1a, which is, however, the smallest one, showed the opposite
behavior, leading to reasonable results only when the reac-
tion was carried out in THF.
Recycling of the catalysts was attempted satisfactorily in
three cases (1b, 1e, and 1f): over three cycles the chemical
yields decreased slowly (likely due to somewhat lower purity
The results obtained from 1g and 1h are congruent with
the mechanism generally accepted18 for catalyzed aldol
(17) (a) Paradowska, J.; Stodulski, M.; Mlynarski, J. Angew. Chem., Int.
Ed. 2009, 48, 4288–4297. (b) Giacalone, F.; Gruttadauria, M.; Lo Meo, P.;
Riela, S.; Noto, R. Adv. Synth. Catal. 2008, 350, 2747–2760. (c) Mase, N.;
Nakai, Y.; Ohara, N.; Yoda, H.; Takae, K.; Tanaka, F.; Barbas, C. F., III
J. Am. Chem. Soc. 2006, 128, 734–735.
(18) (a) Hoang, L.; Bahmanyar, S.; Houk, K. N.; List, B. J. Am. Chem.
Soc. 2003, 123, 16–17. (b) Bahmanyar, S.; Houk, K. N. J. Am. Chem. Soc.
2001, 123, 12911–12912.
J. Org. Chem. Vol. 74, No. 24, 2009 9563

De Nisco et al.
JOCNote
SCHEME 1. Preparation of L-Proline Dipeptide Catalysts 1g and 1h
comparison with 1h, seem to suggest that in the transition
state the ability of the substituent to afford a hydrogen bond
prevails on steric effects.
Brine, in principle, seems to be more effective than water,
although at this stage the results are difficult to rationalize
and still appear somewhat random.
TABLE 4. Solvent and Temperature Effects on Cyclohexanone/
4-Nitrobenzaldehyde Aldol Reactions (48 h) Catalyzed by Compounds
1g and 1h
catalyst mol % solvent T [°C] yield [%]a dr (anti: syn)b ee [%]c
1g
10
3
10
3
10
3
10
3
10
3
10
3
10
3
10
3
water
water
water
water
brine
brine
brine
brine
brine
brine
water
water
water
water
brine
brine
brine
brine
brine
brine
25
25
4
77
51
78
62
96
52
81
79
45
34
99
>99
75
80
>99
>99
96
92:8
91:9
89:11
80:20
92:8
78
75
74
74
81
82
81
78
90
86
56
67
65
67
66
50
75
71
86
77
In conclusion, L-Pro-β3-L-Aaa-OMe dipeptides have been
shown to be promising water-friendly organocatalysts that
present interesting features such as the following: (i) easy
preparation from N-protected L-proline and R-L-amino
acids13 that are both commercially available in enantiomeri-
cally pure form and (ii) modulation of the catalytic activity
through insertion, at C-2 of the starting β3-L-amino acid
methyl ester, of substituents that can be either polar or
nonpolar, and bulky as well.
4
25
25
4
92:8
87:13
92:8
97:3
4
-16
-16
25
25
4
96:4
1h
75:25
77:23
90:10
88:12
72:28
78:22
88:12
88:12
91:9
4
In the near future we intend to hydrolyze19 the protected
carboxyl group of our dipeptides and anchor them to a poly-
meric support, perhaps through a suitable spacer to ensure
rotational freedom of the catalyst species. Work is already in
progress in our lab to improve the performance of the above
more promising catalysts (e.g., 1e and 1f, having Tyr and Trp
side chains, respectively) by playing with different substituents
at the C-2 position of the starting β3-L-amino acid methyl ester.
25
25
4
4
-16
-16
10
3
10
3
97
80
70
90:10
aAfter chromatography. bDetermined by 1H NMR. cDetermined by
HPLC on chiral column.
reactions: as a matter of fact, the polar -NH2 substituent in
1g enables the formation of a hydrogen bond with the
aldehyde carbonyl oxygen whereas the bulky -NHTs group
does not favor the formation of such a bond for both
electronic and stereochemical reasons.14,15 As a conse-
quence, 1g leads to higher enantioselectivity of the nucleo-
phile attack onto the aldehyde carbonyl group.
These results are in rather good agreement with those of
Singh et al.,9b where sulfonamides are shown to be favored
catalysts in aqueous medium. In fact, the introduction of the
-NHTs group at C-2 of the dipeptide 1a increases signifi-
cantly the enatioselectivity of the addition (cf. Table 1 and
the bottom of Table 4).
Experimental Section
General Procedure for Cyclohexanone/4-Nitrobenzaldehyde
Aldol Reaction Catalyzed by Compounds 1a-h. In a 10 mL
round-bottomed flask, equipped with a Teflon-coated stir bar
and some small glass beads, cyclohexanone (2 mmol) was
poured together with the proper solvent (water/brine/dry
THF, 1 mL). 4-Nitrobenzaldehyde (0.5 mmol) and catalyst
(0.05 mmol) were then added in sequence under stirring and
the mixture was gently stirred in the stoppered flask at room
temperature for 48 h. Independently of the solvent used, the
reaction was quenched by addition of 20% aq NH4Cl (5 mL)
and extraction with EtOAc (3 Â 5 mL). The organic layers were
At present, a full comparison of the results appears to be
untimely since our compound 1g (or its analogues) is un-
precedented in catalyzed aldol additions. Its better results, in
(19) (a) Wu, X.-A.; Ying, P.; Liu, J.-Y.; Shen, H.-S.; Chen, Y.; He, L.
Synth. Commun. 2009, 39, 3459–3470. (b) Walton, E.; Rodin, J. O.; Stammer,
C. H.; Holly, F. W. J. Org. Chem. 1962, 27, 2255–2257.
9564 J. Org. Chem. Vol. 74, No. 24, 2009

De Nisco et al.
JOCNote
washed with brine and dried (Na2SO4), and the solvents were
evaporated under reduced pressure. The crude residue was
adsorbed on a preparative layer plate and eluted twice with
hexane:EtOAc (7:3) to separate anti and syn couples. The
residue on the plate was then recovered and flash chromato-
graphed (CHCl3) to get back the catalyst. The ee values were
determined by HPLC on a chiral column.
Acknowledgment. 1H and 13C NMR spectra were per-
formed at Centro Interdipartimentale di Metodologie Chimico-
ꢀ
Fisiche, Universita di Napoli Federico II. The 500 MHz NMR
instrument is the property of Consorzio Interuniversitario
Nazionale la Chimica per l’Ambiente (INCA).
The same procedure was followed for the reactions with use of
0.017 mmol catalyst (3 mmol % loading). Under such circum-
stances, the recovery of catalyst turned out to be unreliable.
All the experiments were duplicated.
Supporting Information Available: Experimental proce-
dures and characterization data of 21 new compounds, 1H and
13C NMR, and HPLC area graphs. This material is available
free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 24, 2009 9565