Simple ionic liquid supported C2-symmetric bisprolinamides as recoverable organocatalysts for the asymmetric aldol reaction in the presence of water

Article abstract of DOI:10.1002/ejoc.201201144

C₂-Symmetric (S)-prolinamides modified with ionic groups and bearing achiral diamine units were synthesized. Their potency as reusable organocatalysts for asymmetric aldol reactions of cycloalkanones or methyl ketones with aromatic (heteroaroma

Full text of DOI:10.1002/ejoc.201201144

FULL PAPER
DOI: 10.1002/ejoc.201201144
Simple Ionic Liquid Supported C2-Symmetric Bisprolinamides as Recoverable
Organocatalysts for the Asymmetric Aldol Reaction in the Presence of Water
Sergei V. Kochetkov,[a] Alexandr S. Kucherenko,[a] Galina V. Kryshtal,[a]
Galina M. Zhdankina,[a] and Sergei G. Zlotin*[a]
Keywords: Aldol reactions / Asymmetric catalysis / Enantioselectivity / Organocatalysis / Water chemistry
C2-Symmetric (S)-prolinamides modified with ionic groups
and bearing achiral diamine units were synthesized. Their
potency as reusable organocatalysts for asymmetric aldol re-
actions of cycloalkanones or methyl ketones with aromatic
(heteroaromatic) aldehydes in the presence of water was
demonstrated. The 1,4-diaminobenzene-derived catalyst ex-
hibited good catalytic performance and excellent recover-
ability over at least 15 reaction–regeneration cycles under
the studied conditions.
afford chiral β-hydroxyketones with high diastereo-
(anti/syn up to 99:1) and enantioselectivity (up to 99%ee).
Unlike the few other known reusable prolinamide-based or-
ganocatalysts that can be used in asymmetric aldol reac-
tions in an aqueous environment,[11] compound 1 retained
its catalytic properties over ten reaction cycles and no cata-
lyst reactivation was needed.
Introduction
Asymmetric organocatalysis is an intensively developing
area of modern organic chemistry.[1] Mimicking natural en-
zymes, small chiral organic molecules[2] used as catalysts al-
low the synthesis of polyfunctional compounds with high
enantiomeric purity from simple prochiral precursors.[3]
The asymmetric aldol reaction is an important enzymatic
(aldolases[4]) and organocatalytic transformation that is
widely used to build carbon–carbon bonds in organic com-
pounds.[5] A number of organocatalysts have been devel-
oped for this reaction[6] over the past decade, and prolin-
amide derivatives are among the most popular and efficient
ones.[7] However, the majority of these catalysts are lost
during product isolation and their commercial application
is challenging.
Figure 1. Supported C2-symmetrical bisprolinamide organocatalyst
1 synthesized previously.
We have recently developed novel C2-symmetric organ-
ocatalyst 1 with the (1R,2R)-bis[(S)-prolinamido]cyclohex-
However, bisamide 1 is a rather complex and expensive
ane unit tagged with two imidazolium+/PF6– ion pairs (Fig- compound that contains six stereocenters. We wondered
ure 1)[8] (references on other reusable proline- and prolin- whether this complexity was compulsory for securing the
amide-type organocatalysts attached to polymers or ionic high stereodifferentiating ability of catalyst 1 or if available
groups are given in ref.[8]). In the presence of this hydro- prolinamides bearing achiral diamine spacers instead of the
phobic catalyst, aromatic or heteroaromatic aldehydes react (1R,2R)-diaminocyclohexane unit would have stereoinduc-
with linear or cyclic ketones in an aqueous medium (a tion and recoverability characteristics similar to those of
“green” solvent,[9] in which natural aldolases “work”[4]) un- catalyst 1. A recently synthesized C2-symmetrical 4-silyl-
der heterogeneous conditions (they were characterized as oxyproline derivative, in which two prolinamide units are
reactions “on water” by Sharpless[10a] and more accurately linked together by a simple –(CH2)6– linker,[7j] displayed
as reactions “in the presence of water” by Hayashi[10b]) to somewhat lower enantioselectivities in asymmetric aldol re-
actions (especially in reactions with a cyclopentanone do-
nor) than C2-symmetrical bisprolinamides containing chiral
binam[7k] or trans-1,2-diamino-1,2-diphenylcyclohexane
scaffolds.[7b] As far as we know, supported C2-symmetrical
prolinamides bearing achiral linkers have not been re-
ported, and their influence on the stereochemical outcome
of a reaction can hardly be predicted. Herein we report the
synthesis of novel ionic liquid supported bisamides 2a–c, in
[a] N. D. Zelinsky Institute of Organic Chemistry,
Russian Academy of Sciences,
119991 Moscow, Russia
Fax: +7-0-499-135-53-28
E-mail: zlotin@ioc.ac.ru
Homepage: http://www.ioc.ac.ru/english/modules/common/
showfile.php?file=labs/lab_11/index
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201144.
Eur. J. Org. Chem. 2012, 7129–7134
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7129

S. G. Zlotin et al.
FULL PAPER
which two prolinamide units are linked together by simple stereocenters in the linker group does not significantly
1,2-diaminobenzene, 1,4-diaminobenzene, and 1,2-diamino- change the stereodifferentiating ability of catalysts 2a–c rel-
ethane linkers, and their catalytic performance in asymmet- ative to that of more sophisticated amide 1.
ric aldol reactions in the presence of water.
Presumably, the prolinamide fragments in the studied
catalysts independently generate the corresponding enamine
intermediates that exhibit no template effect. Furthermore,
similar results obtained in the presence of catalysts bearing
alkylamide (compounds 1 and 2c) or arylamide groups
(compounds 2a and 2b) testify against a direct link between
the nucleophilicity of the amide nitrogen atoms and their
ability to establish stereodiscriminating hydrogen bonds
with aldehyde 10a in transition state 12. Of note is that
bisprolinamides 13 and 14, unlike catalyst 2a, do not con-
tain hydrophobic ionic groups, and they were able to cata-
lyze the model reaction much less efficiently in aqueous me-
dium,[12] which is indicative of the important role of hydro-
phobic interactions between the catalyst, reagents, and
water in heterogeneous complex 12. Additional experiments
showed that the amount of water exerted a negligible im-
pact on the enantioselectivity of the amide 2b-catalyzed
model reaction. However, the anti/syn ratio of aldol product
11a decreased slightly in the system containing 50 equiv. of
H2O or under neat conditions.
Results and Discussion
Compounds 2a–c were synthesized by a scheme compris-
ing amidation of (2S,4S)-N-Cbz-4-hydroxylproline (3) un-
der the action of corresponding diamines 4a–c and Et3N/
EtCO2Cl and esterification of diamides 5a–c with 5-bromo-
valeric acid in the presence of DCC/DMAP [N,NЈ-di-
cyclohexylcarbodiimide/4-(N,N-dimethylamino)pyridine,
Scheme 1]. Subsequent reactions of diesters 6a–c with 1-
methylimidazole followed by metathesis of the anions in re-
sulting salts 7a–c and deprotection of the corresponding
hexafluorophosphates 8a–c (H2, 5% Pd/C) afforded target
catalysts 2a–c. Hydrophobic salts 2a–c are nearly insoluble
in water under normal conditions. They melt at 50–60 °C
and, therefore, can be described as chiral ionic liquids.
At first, we compared the catalytic performance of com-
pounds 2a–c with that of bisprolinamide 1 in the model
reaction of cyclohexanone (9a) with 4-nitrobenzaldehyde
(10a) in the presence of water (Table 1). The reactions were
The final criterion to choose between the three hydro-
carried out without an organic solvent under the hetero- phobic catalysts 2a–c was their recoverability in the on-
geneous conditions (9a/10a = 3:1, 10 mol-% catalyst load- water reaction between compounds 9a and 10a. Upon com-
ing, amount of H2O with respect to 10a = 100 equiv., 24 h, pletion of the reaction (24 h), product 11a was extracted
r.t.). In the presence of catalysts 2a–c and 1, compounds 9a with Et2O, water and fresh reagent portions were added,
and 10a turned completely into a mixture of anti and syn and the reaction was performed once again under the same
isomeric aldol products 11a, in which isomer anti-11a was conditions. The catalytic performances of compounds 2a–c
the key reaction product. The diastereoselectivities of the remained the same in the second cycle (Table 2). However,
reactions catalyzed by amides 2a–c (anti/syn = 92:8–95:5) the activity of catalyst 2c decreased somewhat after the
were higher than the diastereoselectivity obtained in the third cycle and a similar reduced activity of catalyst 2a be-
presence of amide 1 (anti/syn = 90:10), and the enantio- came noticeable after the fifth recovery. Prolinamide 2b
meric enrichment of anti-11a was some 2–3% lower (95– bearing the p-diaminobenzene linker appeared to be the
96% instead of 98%ee). Consequently, the absence of most robust of the studied catalysts. In the reaction between
–
Scheme 1. Synthesis of C2-symmetrical bisprolinamides 2a–c modified with imidazolium cations and PF6 anions.
7130
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 7129–7134

Ionic Liquid Supported C2-Symmetric Bisprolinamides as Organocatalysts
Table 1. Activity and selectivity of catalysts 1 and 2 in the model
reaction between compounds 9a and 10a in the presence of
We then examined the performance of most robust com-
pound 2b (10 mol-%) in asymmetric aldol reactions of vari-
ous ketones and aldehydes in the presence of water
(Table 3). Along with cyclohexanone (9a), 4-methylcyclo-
hexanone (9b) and cyclopentanone (9c) appeared useful
starting compounds. Formyl benzenes 10a–f, in particular
those containing other functional groups in the aromatic
ring, and pyridine and thiophene derivatives 10g–i served
as aldehyde components. In all cases, corresponding aldol
derivatives 11a–o were isolated as the key reaction products.
Cyclohexanone derivatives 9a and 9b generated anti-11a–j
with high diastereoselectivity (anti/syn = 84:16–95:5) and
with good to excellent enantioselectivity (86–98%ee;
Table 3, entries 1–10). The reaction rate depended on the
aldehyde structure: to attain high conversion, the reaction
of 9a with thiophene-2-carbaldehyde (10h) should be car-
ried out at 50 °C, whereas highly electrophilic 5-nitrothio-
phene-2-carbaldehyde (10i) efficiently generated aldol 11i in
the presence of just 1 mol-% of catalyst 2b at room tempera-
ture (Table 3, entry 9). In the reaction with 9a, 4-methoxy-
benzaldehyde (10f) appeared less active than benzaldehyde
(10b) or its derivatives 10a,c–e bearing electron-with-
drawing groups in the aromatic ring. The reaction, when
performed at 50 °C for 72 h, afforded aldol product 11f
with high enantioselectivity (94%ee), however, with incom-
water.[a,b]
Catalyst
(mol-%)
H2O
[equiv.] (with
respect to 10a)
Conv.[c]
[%]
11a dr[c] anti-11a ee[d]
(anti/syn)
[%]
1
plete conversion (Table 3, entry 6). According to H NMR
1[e] (10)
2a (10)
2b (10)
2c (10)
2b (10)
2b (10)
13[f] (5)
14[f] (5)
100
100
100
100
50
0
100
100
99
99
99
99
99
98
92
90
90:10
93:7
95:5
92:8
91:9
89:11
78:22
72:28
98
96
96
95
97
96
71
77
spectroscopy (ref.[13]), the reaction between 4-methylcyclo-
hexanone (9b) and aldehyde 10a proceeded regioselectively
with regard to the C-4 stereocenter in the cyclohexanone
ring to afford 11j. The enantioselectivity of the reaction be-
tween cyclopentanone (9c) and aldehyde 10a was also good,
although in this case syn-aldol product 11k was the main
diastereoisomer (Table 3, entry 11).
[a] Reaction conditions: organocatalyst 1 or 2 (5.3 μmol), 9a
(16 μL, 159 μmol), 10a (8 mg, 53 μmol), and distilled water
(0.1 mL). [b] Broken double-pointed arrows in the scheme desig-
nate the repulsion between the catalyst or hydrophobic structural
fragments of the reagent, and water molecules. [c] Determined by
1H NMR spectroscopic analysis of the crude product. [d] Deter-
mined by HPLC (Chiralcel OJ-H). [e] Data according to ref.[12]
[f] Data according to ref.[8]
Linear methyl ketones 9d–g proved to be also applicable
as starting compounds in amide 2b-catalyzed asymmetric
aldol reactions with aldehyde 10a on water; however, these
reactions had moderate enantioselectivity (30–51%ee) un-
der the studied conditions (Table 3, entries 12–16). The
structural
4-(4-hydroxy-3-methoxyphenyl)butane-2-one
fragment is an integral part of several important biolo-
gically active compounds, in particular of [4]-, [6]-, and [8]-
gingerols and hexahydrocurcumin.[14] This feasible organo-
compounds 9a and 10a catalyzed by 2b that was recycled catalytic approach to chiral aldol products from ketone 9g
14 times, the conversion was 90% and the dr and ee values opens a way to a simple enantioselective synthesis of novel
of product 11a were similar to those obtained for the reac- analogs of these compounds.
tion performed in the presence of freshly prepared catalyst
2b. Presumably, catalyst 2b has a longer lifecycle than 9a
and 9c. This may be attributed to the very small mass loss
that occurs during regeneration of 2b because of its very
Conclusions
limited solubility in diethyl ether, which was used for prod-
In summary, we have synthesized novel ionic liquid sup-
uct extraction (0.068 gL–1 for 2a and 0.018 gL–1 for 2b at ported C2-symmetric amides of (S)-proline bearing simple
1
r.t., see Supporting Information). The H NMR spectrum achiral diamine units and demonstrated their potency as
of the 15-fold regenerated catalyst was nearly identical to efficient catalysts in for asymmetric aldol reactions of
that of the freshly prepared sample, which indicates that the ketones with aromatic (heteroaromatic) aldehydes in the
operation period of catalyst 2b could be longer than 360 h presence of water. The prepared catalysts, which are com-
(15 cycles). The high catalytic performance and recoverabil- parable with the known supported catalysts in terms of ac-
ity of modified prolinamide 2b were demonstrated in ex- tivity and enantioselectivity, are more readily available and
periments performed on a 1-mmol scale (Table 2).
less expensive compounds. The 1,4-bis(prolinamido)benz-
Eur. J. Org. Chem. 2012, 7129–7134
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7131

S. G. Zlotin et al.
FULL PAPER
Table 2. Recoverability of catalysts 2a–c in the model reaction.[a]
Cycle
2a
2b
2c
ee[c,d] [%] Conv.[b] [%] dr[b] (anti/syn)
Conv.[b] [%]
dr[b]
ee[c] [%]
Conv.[b,d]
[%]
dr[b,d]
ee[c] [%]
(anti/syn)
(anti/syn)
1
2
3
4
5
6
7
8
99
97
98
98
99
94
90
82
74
66
63
60
54
50
47
93:7
93:7
93:7
93:7
93:7
94:6
94:6
93:7
95:5
93:7
93:7
94:6
94:6
92:8
92:8
96
95
95
93
94
94
94
94
94
94
94
94
93
94
94
99 (99)
99 (99)
99 (99)
99 (99)
99 (99)
99
98
98
96
93
91
91
91
91
95:5 (95:5)
96:4 (96:4)
96:4 (95:5)
95:5 (96:4)
94:6 (96:4)
94:6
96 (96)
96 (96)
96 (96)
96 (96)
95 (96)
96
96
96
95
96
95
96
96
96
99
95
95
91
87
84
80
76
74
72
–
92:8
92:8
92:8
92:8
93:7
93:7
92:8
92:8
92:8
91:9
–
95
95
94
95
94
94
91
92
92
92
–
94:6
94:6
93:7
94:6
94:6
94:6
94:6
93:7
9
10
11
12
13
14
15
–
–
–
–
–
–
–
–
–
–
–
–
90
93:7
96
[a] The reaction was carried out with amide 9a–c (5.3 μmol), ketone 9a (159 μmol), aldehyde 10a (53 μmol), and distilled water (0.1 mL).
[b] Determined by 1H NMR spectroscopic analysis of the crude product. [c] Determined by HPLC (Chiralcel OJ-H). [d] Data for the
reaction carried out with amide 2b (95 mg, 0.1 mmol), ketone 9a (0.31 mL, 3 mmol), aldehyde 10a (151 mg, 1 mmol), and distilled water
(2 mL) is given in parentheses.
Table 3. A scope of the amide 2b-catalyzed asymmetric aldol reaction on water.[a]
Entry
R1, R2 (9)
R3 (10)
11
Conv.[b] [%]
dr[b] (anti/syn)
ee[c] (anti) [%]
1
2
3
4
–(CH2)4– (a)
4-NO2C6H4 (a)
C6H5 (b)
a
b
c
d
e
f
g
h
i
99
96
99
99
57
17
99
92
99
99
84
99
99
72
67
70
95:5
92:8
95:5
94:6
93:7
86:14
92:8
86:14
84:16
88:12
38:62
–
96
94
97
95
92
94
98
88
–(CH2)4– (a)
–(CH2)4– (a)
4-CNC6H4 (c)
4-MeO2CC6H4 (d)
2-OHCC6H4 (e)
4-MeOC6H4 (f)
2-pyridyl (g)
–(CH2)4– (a)
5
–(CH2)4– (a)
6[d,e]
7[e]
8[d]
9[f]
10
–(CH2)4– (a)
–(CH2)4– (a)
–(CH2)4– (a)
2-thienyl (h)
–(CH2)4– (a)
5-NO2-thienyl (i)
4-NO2C6H4 (a)
4-NO2C6H4 (a)
4-NO2C6H4 (a)
4-NO2C6H4 (a)
4-NO2C6H4 (a)
86
98
–(CH2)2CH(CH3)CH2– (b)
–(CH2)3– (c)
j
k
l
11[f]
12
90 (76)[g]
51
CH3–, H– (d)
CH3(CH2)2–, H– (e)
C6H4CH2CH2–, H–(f)
4-HO(3-CH3O)C6H3CH2CH2–, H– (g) 4-NO2C6H4 (a)
4-HO(3-CH3O)C6H3CH2CH2–, H– (g) C6H5 (b)
13
m
n
–
–
–
–
46
46
30
–
14[h]
15[h]
16[d]
o
[i]
[a] Unless otherwise specified, all reactions were carried out with organocatalyst 9b (5.3 μmol), ketone 10 (159 μmol), aldehyde 11
1
(53 μmol), and distilled water (0.1 mL) at room temperature for 24 h. [b] Determined by H NMR spectroscopic analysis of the crude
product. Yield of the corresponding product isolated by column chromatography on silica was 5–10% lower than the conversion. [c] Deter-
mined by HPLC (Chiralcel OJ-H, OD-H, or Chiralpak AD-H). [d] The reaction was carried out at 50 °C. [e] Reaction time was 72 h.
[f] Catalyst 9b loading was 1 mol-%. [g] Data for syn-aldol product. [h] Reaction time was 48 h. [i] Enone 15 was isolated as the key
reaction product.
ene-derived catalyst displayed excellent recoverability. These
Experimental Section
1
General: The H NMR and 13C NMR spectra were recorded with
a Bruker AM 300 in CDCI3 and [D6]DMSO. Chemical shifts for
1H and 13C were measured relative to Me4Si and CDCl3, respec-
and similar organocatalysts may be useful for developing
novel environmentally friendly technologies for the pro-
duction of chiral biologically active compounds.
7132
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 7129–7134

Ionic Liquid Supported C2-Symmetric Bisprolinamides as Organocatalysts
[4]
a) C. H. Wong, G. M. Whitesides, Enzymes in Synthetic Or-
ganic Chemistry. Pergamon, Oxford, 1994; b) T. D. Machajew-
ski, C. H. Wong, Angew. Chem. 2000, 112, 1406–1430; Angew.
Chem. Int. Ed. 2000, 39, 1352–1374.
tively. HRMS were measured with a Bruker microTOF II spec-
trometer by using electrospray ionization (ESI). The measurements
were taken either in the positive ion mode (interface capillary volt-
age 4500 V) or in the negative ion mode (3200 V) in the mass range
[5]
a) P. I. Dalko (Ed.), Enantioselective Organocatalysis: Reactions
and Experimental Procedures, Wiley-VCH, Weinheim, 2007 b)
A. Berkessel, H. Gröger, Asymmetric Organocatalysis – From
Biomimetic Concepts to Applications in Asymmetric Synthesis
Wiley-VCH, Weinheim, 2005; c) B. List (Ed.), Topics in Current
Chemistry Vol. 291: Asymmetric Organocatalysis, Springer,
Berlin, 2009; d) H. Pellissier, Recent Developments in Asymmet-
ric Organocatalysis, Royal Society of Chemistry, 2010.
a) W. Notz, F. Tanaka, C. F. Barbas III, Acc. Chem. Res. 2004,
37, 580–591; b) S. Saito, H. Yamamoto, Acc. Chem. Res. 2004,
37, 570–579; c) S. Mukherjee, J. W. Yang, S. Hoffmann, B. List,
Chem. Rev. 2007, 107, 5471–5569; d) G. Guillena, C. Nájera,
D. J. Ramón, Tetrahedron: Asymmetry 2007, 18, 2249–2293; e)
J. Mlynarski, J. Paradowska, Chem. Soc. Rev. 2008, 37, 1502–
1511; f) S. G. Zlotin, A. S. Kucherenko, I. P. Beletskaya, Russ.
Chem. Rev. 2009, 78, 737–784; g) B. M. Trost, C. S. Brindle,
Chem. Soc. Rev. 2010, 39, 1600–1632; h) E. Montroni, S. P.
Sanap, M. Lombardo, A. Quintavalla, C. Trombini, D. D.
Dhavale, Adv. Synth. Catal. 2011, 353, 3234–3240; i) E. Mon-
troni, M. Lombardo, A. Quintavalla, C. Trombini, M. Grutta-
dauria, F. Giacalone, ChemCatChem 2012, 4, 1000–1006.
a) Z. Tang, F. Jiang, L. T. Yu, X. Cui, L. Z. Gong, A. Q. Mi,
Y. Z. Jiang, Y. D. Wu, J. Am. Chem. Soc. 2003, 125, 5262–5263;
b) S. Samanta, J. Liu, R. Dodda, C. Zhao, Org. Lett. 2005, 7,
5321–5323; c) Z. Tang, Z. H. Yang, X. H. Chen, L. F. Cun,
A. Q. Mi, Y. Z. Jiang, L. Z. Gong, J. Am. Chem. Soc. 2005,
127, 9285–9289; d) S. Tanimori, T. Naka, M. Kirihata, Synth.
Commun. 2004, 34, 4043–4048; e) Y. Q. Fu, Z. C. Li, L. N.
Ding, J. C. Tao, S. H. Zhang, M. S. Tang, Tetrahedron: Asym-
metry 2006, 17, 3351–3357; f) L. He, J. Jiang, Z. Tang, X. Cui,
A. Q. Mi, Y. Z. Jiang, L. Z. Gong, Tetrahedron: Asymmetry
2007, 18, 265–270; g) X. Liu, L. Lin, X. Feng, Chem. Commun.
2009, 41, 6145–6158; h) X.-H. Chen, J. Yu, L.-Z. Gong, Chem.
Commun. 2010, 46, 6437–6448; i) G. T. Tang, X. M. Hu, H. J.
Altenbach, Tetrahedron Lett. 2011, 52, 7034–7037; j) J. P. De-
laneya, L. C. Henderson, Adv. Synth. Catal. 2012, 354, 197–
204; k) G. Guillena, M. C. Hita, C. Nájera, Tetrahedron: Asym-
metry 2006, 17, 729–733.
from m/z = 50–3000 Da; external or internal calibration was done
with electrospray calibrant solution (Fluka). Syringe injection was
used for solution in methanol (flow rate 3 μLmin–1). Nitrogen was
applied as a dry gas, and the interface temperature was set at
180 °C. Elemental analysis was carried out with a microanalyzer
Perkin–Elmer 2400. IR spectra (KBr pellets) were recorded with a
Specord M82 spectrometer. Silica gel 0.060–0.200 (Acros) was used
[6]
for column chromatography. The solvents were purified by stan-
dard procedures.
General Procedure for the Aldol Reaction: A mixture of ketone 9
(159 μmol), aldehyde 10 (53 μmol), organocatalyst 2a–c (5.3 μmol),
and distilled water (0.1 mL) was stirred at ambient temperature for
24 h. Aldol 11 and the remaining starting compounds were ex-
tracted with Et2O (2ϫ 3 mL), and the combined extract was fil-
tered through a pad of silica gel (1 g) and evaporated under reduced
pressure (15 Torr). Conversions and dr values of aldol products 11
were measured by 1H NMR spectroscopy. The ee values of aldol
products 11 were determined by HPLC (Chiralcel OD–H, OJ–H,
Chiralpak AD–H). NMR spectra and HPLC data for aldol prod-
[7]
ucts 11a–n are available in the cited articles.[15]
Catalyst Recycling: The residue, which was obtained after extrac-
tion of the reaction mixture with Et2O, was dried under reduced
pressure (15 Torr, 60 °C, 30 min). Fresh portions of starting com-
pounds 9a, 10a, and water were added, and the reaction was per-
formed as described above. The experiments were scaled up by
using amide 2b (95 mg, 0.1 mmol), 9a (0.31 mL, 3 mmol), 10a
(151 mg, 1 mmol), and distilled water (2 mL). Upon extraction of
11a with Et2O (5ϫ 5 mL), fresh portions of starting compounds
9a and 10a were added to the remaining suspension of catalyst 2b
in water, and the reaction was performed once again.
Supporting Information (see footnote on the first page of this arti-
1
cle): Procedures for the preparation of each compound; H NMR,
13C NMR, IR, and HRMS spectra and element analysis.
[8]
[9]
S. V. Kochetkov, A. S. Kucherenko, S. G. Zlotin, Eur. J. Org.
Chem. 2011, 6128–6133.
a) C.-J. Li, L. Chen, Chem. Soc. Rev. 2006, 35, 68–82; b) M.
Gruttadauria, F. Giacalone, R. Noto, Adv. Synth. Catal. 2009,
351, 33–57; c) M. Raj, V. K. Singh, Chem. Commun. 2009,
6687–6703; d) N. Mase, C. F. Barbas III, Org. Biomol. Chem.
2010, 8, 4043–4050; e) S. Bhowmick, K. C. Bhowmick, Tetrahe-
dron: Asymmetry 2011, 22, 1945–1979.
Acknowledgments
We gratefully acknowledge financial support of the President of the
Russian Federation (Young PhD Grant MK-3551.2012.3) and of
the Russian Foundation of Basic Research (Grant 12-03-00420).
[10]
[11]
a) S. Narayan, J. Muldoon, M. G. Finn, V. V. Fokin, H. C.
Kolb, K. B. Sharpless, Angew. Chem. 2005, 117, 3339–3343;
Angew. Chem. Int. Ed. 2005, 44, 3275–3279; b) Y. Hayashi, An-
gew. Chem. 2006, 118, 8281–8282; Angew. Chem. Int. Ed. 2006,
45, 8103–8104.
a) M. Gruttadauria, F. Giacalone, A. M. Marculescu, R. Noto,
Adv. Synth. Catal. 2008, 350, 1397–1405; b) M. Gruttadauria,
F. Giacalone, A. M. Marculescu, A. M. P. Salvo, R. Noto, AR-
KIVOC 2009, viii, 5–15; c) T. E. Kristensen, K. Vestli, K. A.
Fredriksen, F. K. Hansen, T. Hansen, Org. Lett. 2009, 11,
2968–2971; d) D. E. Siyutkin, A. S. Kucherenko, S. G. Zlotin,
Tetrahedron 2010, 66, 513–518.
[1] a) P. I. Dalko, L. Moisan, Angew. Chem. 2004, 116, 5248–5286;
Angew. Chem. Int. Ed. 2004, 43, 5138–5175; b) D. W. C. Mac-
Millan, Nature 2008, 455, 304–308; c) A. Dondoni, A. Massi,
Angew. Chem. 2008, 120, 4716–4739; Angew. Chem. Int. Ed.
2008, 47, 4638–4660; d) P. Melchiorre, M. Marigo, A. Carlone,
G. Bartoli, Angew. Chem. 2008, 120, 6232–6265; Angew. Chem.
Int. Ed. 2008, 47, 6138–6171; e) S. Bertelsen, K. A. Jørgensen,
Chem. Soc. Rev. 2009, 38, 2178–2189.
[2] a) B. List, Chem. Commun. 2006, 819–824; b) M. J. Gaunt,
C. C. C. Johansson, A. McNally, N. T. Vo, Drug Discovery To-
day 2007, 12, 8–27; c) X. Yu, W. Wang, Chem. Asian J. 2008,
3, 516–532; d) S. J. Connon, Chem. Commun. 2008, 2499–2510;
e) Y. Takemoto, Chem. Pharm. Bull. 2010, 58, 593–601.
[3] a) R. M. Figueiredo, M. Christmann, Eur. J. Org. Chem. 2007,
2575–2600; b) E. Marqués-López, R. P. Herrera, M.
Christmann, Nat. Prod. Rep. 2010, 27, 1138–1167; c) C. Gron-
dal, M. Jeanty, D. Enders, Nature Chem. 2010, 2, 167–178; d)
O. V. Maltsev, I. P. Beletskaya, S. G. Zlotin, Russ. Chem. Rev.
2011, 80, 1067–1113.
[12]
Z. Lu, H. Mei, J. Han, Y. Pan, Chem. Biol. Drug Des. 2010,
76, 181–186.
[13]
[14]
C. Wu, X. Fu, S. Li, Eur. J. Org. Chem. 2011, 7, 1291–1299.
a) A. Nievergelt, P. Huonker, K. Altmann, J. Gertsch, R.
Schoop, Bioorg. Med. Chem. 2010, 18, 3345–3351; b) C.
Changtam, A. Suksamrarn, H. P. de Koning, H. Ibrahim,
M. S. Sajid, M. K. Gould, Eur. J. Med. Chem. 2010, 45, 941–
956; c) S. Sang, J. Hong, J. Liu, C. S. Yang, H. Wu, C. Ho, M.
Eur. J. Org. Chem. 2012, 7129–7134
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7133

S. G. Zlotin et al.
FULL PAPER
Pan, V. Badmaev, J. Agric. Food Chem. 2009, 57, 10645–10650;
d) J. Lu, S. Guan, X. Deng, G. Xie, X. Shen, W. Qian, G.
Huang, Molecules 2011, 16, 2636–2645.
Z. Gong, J. Am. Chem. Soc. 2005, 127, 9285; d) T. Tanimori,
M. Kirihata, Synth. Commun. 2004, 34, 4043; e) A. Bøgevig,
N. Kumaragurubaran, K. A. Jørgensen, Chem. Commun. 2002,
620; f) D. Mahajan, S. S. Chimni, Indian J. Chem. Sect. B: Org.
Chem. Incl. Med. Chem. 2007, 46, 1355.
[15] a) Z. Tang, F. Jiang, L. T. Yu, X. Cui, L. Z. Gong, A. Q. Mi,
Y. Z. Jiang, Y. D. Wu, J. Am. Chem. Soc. 2003, 125, 5262; b)
S. Samanta, J. Liu, R. Dodda, C. Zhao, Org. Lett. 2005, 7,
5321; c) Z. Tang, Z. Yang, X. Chen, L. Cun, A. Mi, Y. Jiang,
Received: August 21, 2012
Published Online: November 6, 2012
7134
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 7129–7134