Enantioselective Aldol Condensations Catalyzed by Poly(ethylene glycol)-Supported Proline

Full text of DOI:10.1002/1615-4169(20010226)343:2<171::AID-ADSC171>3.0.CO;2-3

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Enantioselective Aldol Condensations Catalyzed
by Poly(ethylene glycol)-Supported Proline
Maurizio Benaglia,a* Giuseppe Celentano,b Franco Cozzia*
a Centro CNR and Dipartimento di Chimica Organica e Industriale, Universita' degli Studi di Milano, via Golgi 19,
20133 Milano, Italy
Fax: (+39) 02-2 66 33 54; e-mail: Franco.Cozzi@unimi.it
b Istituto di Chimica Organica, FacoltaÁ di Farmacia, Universita' degli Studi di Milano, via Venezian 21, 20133 Milano, Italy
Received September 29, 2000; Accepted November 25, 2000
Dedicated to Professor Mauro Cinquini on the occasion of his 60th birthday
Asymmetric catalysis has
witnessed a tremendous
growth in recent years.[1]
While homogeneous pro-
cesses generally secure
best enantioselection, he-
Inexpensive and read-
ily functionalized poly-
(ethylene glycol)s (PEGs)
of Mw ³ 2000 Da feature
the desired solubility pro-
file.[4] We recently re-
Keywords: aldol reactions; asymmetric catalysis;
catalyst immobilization; chiral bases; soluble poly-
mers
terogeneous catalysis allows simple product purifica- ported that a PEG-supported ammonium salt is an ef-
tion and, in principle, catalyst recovery and recycling. ficient, recoverable, and recyclable phase-transfer
In order to combine the advantages of homogeneous catalyst.[5] Here we report that immobilization of
and heterogeneous processes, catalyst immobiliza- (2S,4R)-4-hydroxyproline on PEG5000 monomethyl
tion on polymer matrixes has been investigated.[2] In ether (MeOPEG) by means of a succinate spacer af-
this context, the ideal polymer support should be sol- forded a recyclable catalyst that promoted the enan-
uble in some solvents, for the catalyzed reaction to be tioselective aldol condensation of acetone and hydro-
carried out under best performing conditions, and in- xyacetone with various aldehydes.[6,7]
soluble in other solvents, so that the supported cata-
By reacting MeOPEG monosuccinate 1 (Scheme 1)
lyst, easily isolated and recovered by precipitation with diisopropylcarbodiimide (DIC, 2.2 mol equiv.)
and filtration, can be recycled.[3]
and (2S,4R)-4-hydroxyproline (2.0 mol equiv.) at
140 °C for 20 h in the absence of solvent, diester 2
was obtained in 87% yield.[8] This product was em-
ployed as catalyst (0.3 mol equiv.) for the aldol con-
densation between acetone (68 mol equiv.) and alde-
hydes 3 a±3 d (1.0 mol equiv.) to give aldols 4 a±4 d
(Scheme 1 and Table 1).[6a]
The synthesis of 4 a was selected to establish opti-
mum reaction conditions (entries 1±6). These in-
volved the use of DMF as solvent, and a reaction time
³ 48 h at RT (entry 2). Under these conditions, prod-
uct 4 a was obtained in 68% isolated yield and 77%
enantiomeric excess (ee, by chiral HPLC). These va-
lues nicely compare to those obtained when the re-
action was carried out with (2S,4R)-4-acetoxyproline
as catalyst in DMSO (same reagent ratio) to give 4 a
in 70% yield and 74% ee.[6a] In our case the use of
DMSO instead of DMF (entry 3) gave a higher yield
(73%) but a lower ee (62%) The use of acetone,
CH2Cl2, and toluene slowed down the reaction rate
(entries 4±6). Aldols 4 b and 4 c were also obtained
in yields and ee comparable to those reported (en-
tries 7 and 8).[6a] Remarkably, the reaction could be
extended to aliphatic aldehyde 3 d. Aldol 4 d[9] was
Scheme 1. Synthesis of PEG-supported catalyst 2 and enan-
tioselective aldol condensations
Adv. Synth. Catal. 2001, 343, No. 2
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Table 1. Catalytic enantioselective synthesis of aldols 4 a±d
Entry
Aldehyde
Solvent/Time [h]
Product
Yield (%)[a]
ee (%)[b]
1
2
3 a
3 a
DMF/24
DMF/48
(R)-4 a
(R)-4 a
35
68
67
77
3
4
5
6
7
3 a
3 a
3 a
3 a
3 b
3 c
3 d
3 a
3 a
3 d
DMSO/48
Acetone/48
CH2Cl2/48
Toluene/48
DMF/60
DMF/60
DMSO/130
DMF/48
(R)-4 a
4 a
4 a
73
23
8
15
45
55
81
63
58
77
62
undetermined
undetermined
undetermined
59
63
³ 98
77
77
98
4 a
(R)-4 b
(R)-4 c
(R)-4 d
(R)-4 a
(R)-4 a
(R)-4 d
8
9
10[c]
11[d]
12[e]
DMF/48
DMSO/130
[a] Yields of isolated products. For each aldehyde the highest yields were average values of triplicate experiments run on dif-
ferent scales. The variations in yield were £ 4%.
[b] As determined by HPLC on a chiral stationary phase or by comparison of optical rotation values. Ee values for the highest
yielding reactions were average values of triplicate experiments. The variations in ee were £ 2%.
[c] Carried out with a catalyst sample recycled after use in entry 2.
[d] Carried out with a catalyst sample recycled after use in entries 2 and 10.
[e] Carried out with a catalyst sample recycled after use in entry 8.
obtained in 81% yield and ³ 98% ee (DMSO, RT,
130 h, entry 9).
Experimental Section
Entries 10 and 11 showed that the supported cata-
lyst 2, recovered by precipitation and filtration, could
be recycled two times and employed in the synthesis
of 4 a, with only marginal loss of the catalytic activity
and no erosion of the enantioselectivity. When the
condensation between acetone and aldehyde 3 d was
performed in DMSO with a catalyst sample recycled
RT, dissolved in CH2Cl2 (5 mL), and poured dropwise in Et2O
from the synthesis of 4 c carried out in DMF (entry
Synthesis of Catalyst 2
To a mixture of 1 (3.0 g, 0.6 mmol, loading 0.196 meq/g),
previously dried under vacuum at 90 °C for 1 h, and
(2S,4R)-4-hydroxyproline (0.156 g, 1.2 mmol) kept at 140 °C
under N2, DIC (0.204 mL, 1.32 mmol) was added dropwise.
After 20 h stirring at 140 °C, the thick mixture was cooled at
(200 mL). The precipitated pale brown solid was filtered,
8), aldol 4 d was obtained in 77% yield and 96% ee
(entry 12), thus showing the generality of catalyst re-
covery and recycling.
washed first with Et2O (150 mL) and then with ice-cold ab-
solute EtOH (150 mL), and dried under vacuum to give 2
(2.67 g, 0.52 mmol, loading 0.191 meq/g). 1H-NMR
(300 MHz, CDCl3, with pre-saturation of the PEG methylene
signals at d = 3.63; relaxation delay: 6 s; acquisition time:
4 s): d = 5.58±5.67 (1 H, m, H-C4 of proline), 4.25 (2 H, t,
J = 4.4 Hz, PEG-CH2OCO), 4.00±4.17 (1 H, m, H-C2 of pro-
line), 3.30 (3 H, s, CH3O), 2.66 (2 H, t, J = 6.8 Hz, CH2COO-
proline), 2.58±2.70 (2 H, m, H2C3 of proline), 2.44 (2H, t,
J = 6.8 Hz, CH2CH2COO-proline).
In subsequent experiments it was found that cata-
lyst 2 (0.25 mol equiv.) also promoted the enantio-
and diastereoselective condensation of hydroxyace-
tone with aldehyde 3 d (Scheme 1). Thus, anti-aldol 5
(anti/syn ratio > 20/1) was obtained (DMF, RT, 48 h) in
48% yield and ³ 98% ee. With non-supported proline
as catalyst (same reagent ratio, DMSO as solvent) this
reaction gave 5 in 60% yield, > 99% ee, and anti/syn
ratio > 20/1.[6b]
General Procedure for the Aldol Condensation
In conclusion, these results showed that a modified
PEG is a convenient catalyst support for a syntheti-
cally relevant enantioselective aldol condensation
process. The PEG-supported catalyst secured high le-
vel of stereocontrol (up to ³ 98% ee), very similar to
those obtained with the non-supported catalyst. Very
simple catalyst recovery and recycling was also de-
monstrated. These findings can be useful in design-
ing practical enantioselective catalytic reactions with
continuous catalyst recycle. The generality of the use
of PEG as a ``harmless'' chiral catalyst support in other
enantioselective transformations is currently being
investigated in our laboratories.
The synthesis of 4 a is illustrative of the procedure. To a stir-
red solution of catalyst 2 (0.160 g, 0.0306 mmol), previously
dried under vacuum at 90 °C for 1 h, in dry DMF (2 mL) and
acetone (0.5 mL, 6.8 mmol), 4-nitrobenzaldehyde (0.0151 g,
0.1 mmol) was added in one portion. The mixture was stir-
red at RT for 48 h and then poured in Et2O (100 mL). The
precipitated 2 was filtered off, and the solid was washed with
Et2O (50 mL). Average recovery of catalyst ranged from 70 to
80% (0.110 to 0.130 g) when the reaction was run on the
above-mentioned scale, and increased to ³ 90% when the re-
action was run on a doubled or an even larger scale. The fil-
trate was washed twice with water, and the Et2O phase was
dried and concentrated. The residue was purified by flash
chromatography with a 1 : 1 hexanes: Et2O mixture as eluant
to give the product (0.010 g, 68%), that had 1H-NMR data in
172
Adv. Synth. Catal. 2001, 343, 171±173

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agreement with those reported. The ee was determined by
HPLC (Daicel Chiralpack AS, hexane/i-PrOH = 70:30, flow
rate 0.8 mL/min, l = 270): tR: 13.285 min (major) and
15.942 min (minor). [a]2D3: + 55.3° (c 0.2, in CHCl3).
Aldols 4 a±4 d and 5 were known compounds. They had
spectral data in agreement with those reported. Their abso-
lute configuration was assigned on the basis of comparison
of optical rotation sign.
[5] R. Annunziata, M. Benaglia, M. Cinquini, F. Cozzi,
Org. Lett. 2000, 2, 1737±1739.
[6] These intermolecular aldol condensations catalyzed by
proline and proline derivatives have recently been de-
scribed: (a) B. List, R. A. Lerner, C. F. Barbas, III, J.
Am. Chem. Soc. 2000, 122, 2395±2396; (b) W. Notz,
B. List, J. Am. Chem. Soc. 2000, 122, 7386±7387; for ex-
amples of proline±catalyzed intramolecular aldol-type
processes see: (c) U. Eder, G. Sauer, R. Weichert, An-
gew. Chem. Int. Ed. Engl. 1971, 10, 496±497; (d) Z. G.
Hajos, D. R. Parrish, J. Org. Chem. 1974, 39, 1615±
1621; (e) T. Bui, C. F. Barbas, III, Tetrahedron Lett.
2000, 41, 6951±6954.
[7] For the immobilization of chiral ligands on soluble
polymers see: (a) C. Bolm, A. Gerlach, Angew. Chem.
Int. Ed. Engl. 1997, 36, 741±743; (b) H. Han, K. D. Jan-
da, Angew. Chem. Int. Ed. Engl. 1997, 36, 1731±1733;
(c) Q. Fang, C. Ren, C. Yeung, W. Hu, A. S. C. Chan, J.
Am. Chem. Soc. 1999, 121, 7407±7408; (d) C. Bolm.,
C. L. Dinter, A. Seger, H. HoÈcker, J. Brozio, J. Org.
Chem. 1999, 64, 5730±5731; (e) T. S. Reger, K. D. Jan-
da, J. Am. Chem. Soc. 2000, 122, 6929±6934;
(f) M. Glos, O. Reiser, Org. Lett. 2000, 2, 2045±2048.
For the use of fluorous biphase systems as solubility
device in this context, see: (g) G. Pozzi, F. Cinato,
F. Montanari, S. Quici, Eur. J. Org. Chem. 1999, 1947±
1955.
Acknowledgements
This work was supported by CNR and MURST (Progetto Na-
zionale Stereoselezione in Sintesi Organica. Metodologie ed
Applicazioni).
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