Dipeptide-catalyzed asymmetric aldol condensation of acetone with (N-alkylated) isatins

Article abstract of DOI:10.1021/jo050257l

The aldol condensation of acetone with several isatins is described. The desired compound was obtained in quantitative yield and with good enantioselectivities up to 77%. The best results were obtained with 10 mol % H-D-Pro-L-β³-hPhg-OBn as a c

Full text of DOI:10.1021/jo050257l

SCHEME 1. Aldol Reaction of Isatin with Acetone
Dipeptide-Catalyzed Asymmetric Aldol
Condensation of Acetone with
(N-Alkylated) Isatins
Gianluigi Luppi,† Pier Giorgio Cozzi,† Magda Monari,†
Bernard Kaptein,‡ Quirinus B. Broxterman,‡ and
Claudia Tomasini*,†
TABLE 1. Enantiomeric Excesses and Yields of 1a
Formed in the Aldol Reaction of Isatin with Acetone
Catalyzed by L-Proline and L-Prolinamidea
Dipartimento di Chimica “G. Ciamician”, Alma Mater
Studiorum Universita` di Bologna, Via Selmi 2,
40126 Bologna, Italy, and Life Sciences, Advanced Synthesis
& Catalysis, DSM Research, P.O. Box 18,
time temp
(h) (°C)
ee configur-
entry
catalyst
H-L-Pro-OH
H-L-Pro-NH2
yield (%) (%)b ation
1
2
3
4
90 -15 quantitative 33
S
S
R
S
6160 MD Geleen, The Netherlands
2
16
20 82
20 25
20 48
23
30
17
cis-4-OH-D-Pro-OH
trans-3-OH-L-Pro-OH 16
claudia.tomasini@unibo.it
Received February 8, 2005
a Conditions: concentration of isatin in acetone is 0.15 M, and
10 mol % catalyst was used. b Ee values were determined by
HPLC.
but to the best of our knowledge no reactions have been
reported on ketones yet.3
In this paper we want to describe the results obtained
on the aldol condensation of acetone with isatin and
N-alkylated isatins. This reaction enables the formation
of a quaternary stereogenic center with good enantiose-
lectivity (Scheme 1). The product 1a had already been
prepared in the racemic form, but no synthesis of the
enantiopure form has yet been described.4
Highly polar solvents such as DMSO and DMF are
often used in organocatalysis reaction due to the low
solubility of proline, which is routinely used as a catalyst
in up to 20-30 mol %. Since such high-boiling solvents
are difficult to remove at the end of the reaction, the use
of acetone not only as a reagent but also as a solvent is
advantageous due to its ease of removal. Further, the
identification of new catalysts with increased solubility
is highly desirable.
The aldol condensation of acetone with several isatins is
described. The desired compound was obtained in quantita-
tive yield and with good enantioselectivities up to 77%. The
best results were obtained with 10 mol % H-D-Pro-L-â3-hPhg-
OBn as a catalyst, resulting in the preferential formation
of the (R)-enantiomer. The absolute configuration of the
newly formed chiral center has been assigned by an X-ray
diffraction study and CD spectra analysis of the molecules.
The reaction was initially investigated using L-proline
as a catalyst (Table 1, entry 1). In a typical reaction, the
catalyst (0.03 mmol) was dissolved in acetone and the
mixture stirred at -15 °C. After 15 min, solid isatin (0.3
mmol) was added and the mixture stirred at -15 °C for
90 h. After this time, the mixture was concentrated and
analyzed by HPLC equipped with a chiral column.
The aldol condensation is an important reaction for the
formation of new carbon-carbon bonds, both in synthetic
organic chemistry and in nature. The use of the inex-
pensive and nontoxic proline as a catalyst in reactions
involved in enamine formation was first introduced by
Hajos and Parrish and also independently by Eder,
Sauer, and Wiechert.1 This reaction has subsequently
been widely studied by List.2 Recently, many research
groups have tested various oligopeptides containing
proline as an N-terminal amino acid as catalysts in the
aldol condensation and related reactions of aldehydes,
The reaction using L-proline as a catalyst afforded the
desired compound 3-(2-oxopropyl)-3-hydroxyindolin-2-one
(3) Organocatalytic reactions mediated by oligopeptides, see: (a)
Kofoed, J.; Nielsen, J.; Reymond, J.-L. Bio. Chem. Med. Lett. 2003,
13, 2445-2447. (b) Jarvo, E.; Miller, S. J. Tetrahedron 2002, 58, 2481-
2495. (c) Shi, L.-X.; Sun, Q.; Ge, Z.-M.; Zhu, Y.-Q.; Cheng, T.-M.; Li,
R.-T. Synlett 2004, 2215-2217. (d) Tang, Z.; Yang, Z.-H.; Cun, L.-F.;
Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z. Org. Lett. 2004, 6, 2285-2287. (e)
List, B.; Martin, H. J. Synlett 2003, 1901-1902.
(4) For the racemic aldol condensation of isatins with methylketones,
see: (a) Kawasaki, T.; Nagaoka, M.; Satoh, T.; Okamoto, A.; Ukon, R.;
Ogawa, A. Tetrahedron 2004, 60, 3493-3503. (b) Garner, S. J.; da
Silva, R. B.; Pinto, A. C. Tetrahedron 2002, 58, 8399-8412. (c) Beccalli,
E. M.; Marchesini A.; Pilati, T. J. Chem. Soc., Perkin Trans. 1 1994,
579-587.
* Phone: +39-051-2099511. Fax: +39-051-2099456.
† Alma Mater Studiorum Universita` di Bologna.
‡ DSM Research.
(1) (a) Hajos, Z. G.; Parrish, D. R.. J. Org. Chem. 1974, 39, 1615-
162. (b) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. Engl.
1971, 10, 496-497.
(2) List, B. Acc. Chem. Res. 2004, 37, 548-557, and refs therein.
For a recent review, see: Dalko, P.; Moisan, P. Angew. Chem., Int.
Ed. 2004, 43, 5138-5175.
10.1021/jo050257l CCC: $30.25 © 2005 American Chemical Society
Published on Web 08/05/2005
7418
J. Org. Chem. 2005, 70, 7418-7421

TABLE 2. Enantiomeric Excesses and Yields of 1a
Formed in the Aldol Reaction of Isatin with Acetone
Catalyzed by Dipeptides 2-16a
cata- time temp
ee
configur-
ation
entry
lystb
(h)
(°C)
yield (%)
(%)c
1
2
2
3
19
19
20
20
17
16
26
16
17
17
19
15
23
64
16
16
64
64
64
16
17
16
-15
-15
-15
-15
-15
20
80
46
56
43
22
43
20
S
S
S
S
S
S
quantitative
3
4
92
96
4
5
5
6
quantitative
quantitative
6
7
7
8
20
0
96
8
9
-15
-15
-15
-15
-15
20
67
47
4
S
S
R
R
R
R
R
R
R
R
R
R
R
R
R
9
10
11
12
13
13
13
13
13
13
13
13
14
15
16
quantitative
10
11
12
13
14e
15d
16d,e
17d,e
18
19d
20
21
22
23
quantitative
49
72
55
56
73
64
73
63
68
48
49
32
92
quantitative
20
70
-15
-15
-15
-50
-50
-15
-15
20
quantitative
45
quantitative
30
60
88
quantitative
42
a Unless otherwise specified, the concentration of isatin in
acetone was 0.15 M. b Unless otherwise stated, the catalyst loading
was 10 mol %. c Ee values were determined by HPLC. d Performed
with a 1 M concentration of isatin in acetone. e Catalyst loading
was 1 mol %.
FIGURE 1. Dipeptides evaluated in this study.
1a in quantitative yield but with low enantioselectivity,
33%. A disappointing outcome was also obtained not only
using L-prolinamide 5 as a catalyst but also using differ-
ent hydroxyprolines (entries 2-4). In these cases, the
reactions were carried out at 20 °C because only starting
material was recovered at -15 °C, probably owing to the
low solubility of the catalysts at low temperature.
In view of these results, we investigated the use of
dipeptides containing N-terminal proline residues as
catalysts: 15 dipeptides with the general formula L- or
D-“Pro”-Xaa-OR, where Xaa is a natural or an unnatural
amino acid (Figure 1), were prepared by conventional
peptide synthesis starting from the Boc-protected “pro-
line”-amino acid. After synthesis, the Boc-protecting
group was removed using TFA in methylene chloride.
Thus, dipeptides containing R,R-disubstituted amino
acids such as L-(RMe)Pro [L-(R-methyl)proline], Aib (R-
aminoisobutyric acid), or L-(RMe)Chg [L-(R-methyl)cyclo-
hexylglycine]6 and dipeptides containing â-amino acids
such as L-â3-hVal (L-â3-homovaline), L-â3-hPhg (L-â3-
homophenylglycine), or D-â2-hPhe (D-â2-homophenylala-
nine)7 were tested as catalysts for the reaction of isatin
with acetone under the same reaction conditions as
reported above, and the results are shown in Table 2.
These results are a substantial improvement on those
reported in Table 1: an enantiomeric excess as high as
73% was obtained when H-D-Pro-L-â3-hPhg-OBn 13 was
used as a catalyst. Remarkably, the concentration of the
isatin has nearly no effect on the ee, probably due to the
high solubility of the catalyst. Hence, similar ees were
obtained whether using 0.15 or 1 M solutions (cf. entry
12 with 15 and entry 18 with 19). However, attempts to
increase the enantiomeric excess by lowering the tem-
perature (cf. entry 12 with 18 and entry 15 with 19) were
unsuccessful.
Noteworthy results were obtained with 1 mol %
catalyst (cf. entry 13 with 14 and entry 15 with 16 and
17): at -15 °C, after prolonged reaction times (entry 17),
the reaction occurred in quantitative yield and with the
same enantiomeric excess as obtained with 10 mol %
catalyst (entry 15). It is also noteworthy that the reaction
catalyzed by H-L-Pro-L-â3-hPhg-OBn 9 (epimer of 13)
(entry 8) produced the opposite enantiomer, although
with a slightly lower ee.
Some interesting conclusions can be drawn: The
absolute configuration of proline is determining the sign
of the enantiomeric excess, but an accurate choice of the
amino acid in the second position is indispensable:
indeed, highly hindered amino acids furnish mediocre
results (cf. entry 2 with 4). Furthermore, replacing
proline with â-homoproline yields the worst results, while
â-amino acids in the second position in general give better
results than R-amino acids.
To determine the absolute configuration of the newly
formed stereogenic center, two samples of 1a (those
obtained from entries 8 and 15) were purified with silica
gel chromatography (eluent ) cyclohexane/ethyl acetate
8:2). During the purification, an enantiomeric enrichment
(5) For the use of prolinamide as a catalyst, see: (a) Tang, Z.; Jiang,
F.; Cui, X.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z.; Wu, Y.-D. PNAS 2004,
101, 5755-5760. (b) Marigo, M.; Bachmann, S.; Halland, N.; Braunton,
A. Jo¨rgensen, K. A. Angew. Chem., Int. Ed. 2004, 43, 5507-5510. (c)
Wang, W.; Wang, J.; Li, H. Org. Lett. 2004, 6, 2817-2820.
(6) (a) Formaggio, F.; Moretto, V.; Crisma, M.; Toniolo, C.; Kaptein,
B.; Broxterman, Q. B. J. Peptide Res. 2004, 63, 161-170. (b) Kruizinga,
W. H.; Bolster, J.; Kellogg, R. M.; Kamphuis, J.; Boesten, W. H. J.;
Meijer E. M.; Schoemaker H. E. J. Org. Chem. 1988, 53, 1826-1827.
(c) Kaptein, B.; Boesten, W. H. J.; Broxterman, Q. B.; Peters, P. J. H.;
Schoemaker H. E.; Kamphuis, J. Tetrahedron: Asymmetry 1993, 4,
1113-1116.
(7) (a) Boesten, W. H. J.; Moody, H. M.; Kaptein, B.; Seerden, J. P.
G.; van der Sluis, M.; de Lange, B. (DSM). PCT Pat. Appl. WO 01/
42173. (b) Broxterman, Q. B.; Kaptein, B.; Kierkels J. G. T.; Milcent,
T. J. A. (DSM) Eur. Pat. Appl. No. 04075597.7 (patent pending).
J. Org. Chem, Vol. 70, No. 18, 2005 7419

TABLE 3. Aldol Reaction of N-Alkylated Isatin
Derivatives with Acetone-Catalyzed by Dipeptide 13
a
pro- time temp concn
R′ duct (h) (°C) (M)
ee (R) configur-
entry
R
yield (%)
(%)b
ation
1
2
3
4
Me H 1b
17 -15 0.15 quantitative 77
R
R
R
R
Et
Bn
H
H
H
1c
1d
16 -15 0.15 92
17 -15 0.15 90
74
74
Br 1e
17 -15 0.15 quantitative 73
a Concentration of the isatin in acetone was 0.15 M. b Ee values
were determined by HPLC.
FIGURE 2. CD spectra of sample A and sample B of 1a
(solution 5 mM in methanol).
of the products occurred, and a sample from entry 8 with
87% ee (sample A) and a sample from entry 15 with 84%
ee (sample B) of the opposite enantiomer could be
isolated. Similar enantiomeric enrichment of nonracemic
mixtures during chromatographic purifications has al-
ready been observed by other research groups and has
been ascribed to stable diastereomeric interactions be-
tween the two enantiomers.8
The two samples were analyzed by CD spectroscopy
(Figure 2): in the CD spectra, sample A exhibits a
negative Cotton effect in the long-wave region (300-255
nm) and a positive effect in the short-wave region (260-
220 nm), while sample B exhibits exactly the opposite
behavior.
FIGURE 3. ORTEP drawing of the (R)-enantiomer of 1e (30%
thermal ellipsoids).
This outcome has been compared with the CD spectra
of the two diastereomers of (2S,3R)- and (2S,3S)-3-
hydroxytryptophan reported by Aimi and co-workers.9
They assigned the absolute configuration of the quater-
nary stereogenic center of isorhynchophylline by compar-
ing the CD spectra of both enantiomers (of a known
derivative) with the CD spectra of (2S,3R)- and (2S,3S)-
3-hydroxytryptophan. Indeed (2S,3S)-hydroxytryptophan
([R]D -19.9°) exhibits a negative Cotton effect in the long-
wave region (280-255 nm) and a positive effect in the
short-wave region (260-220 nm), while the other dias-
tereomer ([R]D +36.7°) having the (2S,3R)-configuration
showed exactly the opposite behavior.
Thus, comparison of the CD spectra of our samples
with the reported data allows us to state that sample A
has (S)-absolute configuration and sample B has (R)-
absolute configuration and thus that the catalysts con-
taining L-Pro induce the formation of the (S)-enantiomer,
while the catalysts containing D-Pro induce the formation
of the (R)-enantiomer.
FIGURE 4. Crystal packing of 1e showing the zigzag chain
generated by the intermolecular hydrogen bonds running along
the b-axis.
The absolute configuration of 1e was unambiguously
determined by single-crystal X-ray investigations carried
out on crystals grown from slow evaporation of a chlo-
roform solution. We obtained two sets of crystals, having
different habits, which turned out to be the racemic
mixture (as platelets) and the pure enantiomer (as
needles). X-ray analysis of the needles showed that the
absolute configuration of the stereogenic center was (R)-
(Figure 3). HPLC analysis of the crystal confirmed that
it is the more abundant enantiomer, which is the second
to be eluted.
Finally, we tested the efficiency of H-D-Pro-L-â3-hPhg-
OBn 13 in the addition of acetone to N-alkylated isatins
and 5-bromoisatin (Table 3).10 The syntheses of the race-
mic products 1b and 1d have already been described.4b,11
Entries 1-4 show that in each case a good ee was
obtained with the preference for the (R)-enantiomer.
(8) See for example: (a) Stefani, R.; Cesare, V. J. Chromat. A. 1998,
813, 79-84. (b) Lozˇa, E.; Lo¨ıa D.; IÄemme, A.; Freimanis, J. J.
Chromatogr. A. 1995, 708, 231-243.
(9) Takayama, H.; Shimizu, T.; Sada, H.; Harada, Y.; Kitajima, M.;
Aimi, N. Tetrahedron 1999, 55, 6841-6846.
Interestingly, in the crystal packing of the (R)-enan-
tiomer, the molecules formed zigzag chains via intermo-
lecular N-H...O and O-H...O hydrogen bonds (Figure
4) not involving the ketonic oxygen of the lateral chain.
(10) Azizian, J.; Fallah-Bagher-Shaidaci, H.; Kefayati, H. Synth.
Commun. 2003, 33, 789-793.
(11) Krishna, C.; Kundu, A. K.; Pranab, C. J. Chem. Res., Synop.
1996, 10, 460-461.
7420 J. Org. Chem., Vol. 70, No. 18, 2005

and the mixture was stirred for the time described in the
appropriate table. After this time, acetone was removed under
reduced pressure, and the mixture was purified by flash chro-
matography (cyclohexane/ethyl acetate 1:1) to eliminate the
catalyst. The enantiomeric excesses were determined by chiral
HPLC prior to purification. Analytical high-performance liquid
chromatography (HPLC) was performed on an HP 1090 liquid
chromatograph equipped with a variable-wavelength UV detec-
tor (deuterium lamp 190-600 nm), using a Daicel CHIRALPAK
AD column (0.46 cm i.d. x 25 cm) (Daicel, Inc.) (for the analysis
of 1a) or a Daicel CHIRALCEL OD column (0.46 cm i.d. x 25
cm) (Daicel, Inc.) (for the analysis of 1b-d). Hexane CHROMA-
SOLV and 2-propanol CHROMASOLV for HPLC were pur-
chased from Riedel-de Hae¨n and used as the eluting solvents.
The CD spectra were obtained on a Jasco J-810 spectropolarim-
eter. Cylindrical fused quartz cells of 0.05 and 0.02 cm path
length were used. The values are expressed in terms of molecular
CD.
3-(2-Oxopropyl)-3-hydroxyindolin-2-one 1a. IR (Nujol): ν
1
) 3363, 3318, 1719, 1624 cm-1. H NMR (300 MHz, CDCl3): δ
2.20 (s, 3H), 3.03 (d, 1H, J ) 17.1 Hz), 3.23 (d, 1H, J ) 17.1
Hz), 4.81 (bs, 1H), 6.91 (d, 1H, J ) 7.5 Hz), 7.07 (t, 1H, J ) 7.5
Hz), 7.24-7.39 (m, 2H), 8.43 (bs, 1H). 13C NMR (75 MHz,
CDCl3): δ 31.4, 48.8, 74.5, 110.5, 123.1, 124.2, 128.5, 130.1,
140.6, 178.2, 207.5. MS (EI) m/z (rel intensity): 206 (M+ + 1),
188, 146. HRMS (EI): calcd for C11H11NO3 (M+ + 1) 206.0817,
found 206.0829.
FIGURE 5. CD spectra of samples of 1a-e (concentration 5
mM in methanol).
Chiral HPLC analysis showed a general preference for
the formation of the (R)-isomer, analogously to what was
observed for 1a. To corroborate this deduction, enriched
fractions of 1b-e were obtained by silica gel chromatog-
raphy, thus showing that the enantiomeric enrichment
during chromatographic purifications of nonracemic mix-
tures of these (N-alkylated) isatins is a general effect for
these isatin derivatives, and the CD spectra were re-
corded and compared with those of (R)-1a and (R)-1e.
The spectra shown in Figure 5 are nearly superimpos-
able.
In summary, we have described the asymmetric aldol
condensation of acetone with isatin, its N-alkylated
derivatives, and 5-bromoisatin. A new quaternary ste-
reocenter is obtained with good enantioselectivity (up to
77%), which can easily be enriched by silica flash chro-
matography; this effect proved to be general for this class
of compounds. The best dipeptide catalysts turned out
to be derived from proline and â3-homophenylglycine.
Acknowledgment. C.T. and G.L. thank MIUR
Cofin 2002 (“Sintesi di peptidi ciclici o lineari contenenti
amminoacidi inusuali analoghi di arginina, glicina o
acido aspartico (RGD) come nuovi inbitori di integrine”),
FIRB 2001 (“Eterocicli azotati come potenziali inbitori
enzimatici”) and Ricerca Fondamentale Orientata (60%),
and the University of Bologna (funds for selected topics
“Processi di sintesi innovativi ed eco-compatibili di
molecole bioattive”) for financial support. P.G.C. is
grateful to LigBank (the European Ligand Bank) and
MIUR (“Progetto nazionale Stereoselezione in Chimica
organica, metodologie ed applicazioni”) for financial
support. G.L. thanks Consorzio C.I.N.M.P.I.S. (Bari) for
a grant.
Supporting Information Available: Experimental de-
tails and characterization of the isatin derivatives 1a-d and
1
the catalysts 2-16; H NMR and 13C NMR spectral data for
1a-d; and X-ray crystallographic data (CIF), experimental
crystallographic details, and ORTEP drawings for 1e. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Experimental Section
General Method for the Synthesis of 1-Alkyl 3-(2-
Oxopropyl)-3-hydroxyindolin-2-ones. The ligand (0.03 mmol)
was stirred in acetone (2 mL) for 15 min at the temperature
described in Table 1, 2, or 3. Solid isatin (0.3 mmol) was added,
JO050257L
J. Org. Chem, Vol. 70, No. 18, 2005 7421