Zn(pybox)-complex-catalyzed asymmetric aqueous Mukaiyama-Aldol reactions

Article abstract of DOI:10.1021/jo0514568

Catalytic asymmetric aldol reactions in aqueous media have been developed using chiral zinc complex. The aldol products have been obtained in high yields, high diastereocontrol, and good level of enantioselectivity. Various aromatic and α,β-unsaturated al

Full text of DOI:10.1021/jo0514568

Zn(pybox)-Complex-Catalyzed Asymmetric Aqueous
Mukaiyama-Aldol Reactions
Joanna Jankowska and Jacek Mlynarski*
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
mlynar@icho.edu.pl
ReceiVed July 14, 2005
Catalytic asymmetric aldol reactions in aqueous media have been developed using chiral zinc complex.
The aldol products have been obtained in high yields, high diastereocontrol, and good level of
enantioselectivity. Various aromatic and R,â-unsaturated aldehydes and silyl enol ethers derived from
ketones can be employed in this reaction to provide the aldol adducts in good to high yield. The elaborated
catalytic system has been found as selective for aliphatic aldehydes as well.
7
Introduction
can act as Lewis acid type catalysts in aqueous medium. In
this way a number of diastereoselective Mukaiyama-type aldol
The aldol reaction is well recognized as one of the most
important carbon-carbon bond-forming methods in organic
synthesis. Up to two stereogenic centers are generated in the
reaction, and thus a useful protocol must fulfill satisfactory levels
of the reaction yield, diastereoselectivity, and enantioselectivity.
Among other recently elaborated methods, aldol reaction of
8
reactions were realized using lanthanide triflates and other
water-compatible metals salts, avoiding the use of rigorously
9
dried and potentially toxic solvents and allowing the easy
recovery of the active Lewis acid catalyst.
Enantioselective versions of Lewis acid mediated reactions
in aqueous solvents are challenging especially in the context of
designing a chiral ligand with appropriate binding property to
the metal cations. The catalysts containing copper, lead, and
gallium have been used with some success in enantioselective
aqueous Mukaiyama-aldol reactions. The most spectacular
success in this area was the application of rare earth metal
elements. Kobayashi and co-workers developed the combination
of praseodymium triflate and chiral crown ethers for asymmetric
1
2
3
aldehydes with silicon enolates, the Mukaiyama reaction, has
been recognized as one of the most convenient and valuable.
4
6
10
11
Although several successful examples of chiral Lewis acid
catalyzed Mukaiyama reactions have been developed, most of
them have to be conducted at low temperatures in aprotic
anhydrous solvents.
Stereoselective organic transformations in aqueous media
have recently attracted a great deal of attention because
environmental protection demands clean reaction processes that
12
(
6) (a) Lindstr o¨ m, U. M. Chem. ReV. 2002, 102, 2751. (b) Sinou, D.
AdV. Synth. Catal. 2002, 344, 221. (c) Manabe, K.; Kobayashi, S. Chem.
Eur. J. 2002, 8, 4095. (d) Kobayashi, S.; Manabe, K. Acc. Chem. Res. 2002,
35, 209.
5
do not use damaging and expensive organic solvents. Many
carbon-carbon bond-forming processes have been carried out
6
(7) (a) Kobayashi, S. Synlett 1994, 689. (b) Kobayashi, S. In Lan-
thanides: Chemistry and Use in Organic Synthesis; Kobayashi, S., Ed.;
Springer: Berlin, 1999; p 63. (c) Kobayashi, S.; Sugiura, M.; Kitagawa,
H.; Lam, W. W.-L. Chem. ReV. 2002, 102, 2227.
(8) (a) Kobayashi, S. Chem. Lett. 1991, 2187. (b) Kobayashi, S.; Hachiya,
I. J. Org. Chem. 1994, 59, 3590.
in water since Kobayashi showed that rare earth metal triflates
*
To whom correspondence should be addressed. Fax: +48 22 632 66 81.
1) Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH: Weinheim
004.
(
2
(
2) (a) Machajewski, T. D.; Wong, C.-H. Angew. Chem., Int. Ed. 2000,
(9) (a) Kobayashi, S.; Nagayama, S.; Busujima, T. J. Am. Chem. Soc.
1998, 120, 8287. (b) Mu n˜ oz-Mu n˜ iz, O.; Quintanar-Audelo, M.; Juaristi, E.
J. Org. Chem. 2003, 68, 1622.
3
2
9, 1352. (b) Palomo, C.; Oiarbide, M.; Garcia, J. M. Chem. Soc. ReV.
004, 33, 65.
(
(
3) Mukaiyama, T.; Narasaka, K. Banno, K. Chem. Lett. 1973, 1012.
4) (a) Mukaiyama, T. Org. React. 1982, 28, 203. (b) Mukaiyama, T.;
(10) Kobayashi, S.; Nagayama, S.; Busujima, T. Tetrahedron 1999, 55,
8739.
Matsuo, J. In Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH:
Weinheim 2004; p 127.
(11) Nagayama, S.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 11531.
(12) (a) Li, H.-J.; Tian, H.-Y.; Chen, Y.-J.; Wang, D.; Li, Ch.-J. Chem.
Commun. 2002, 2994. (b) Li, H.-J.; Tian, H.-Y.; Wu, Y.-Ch.; Chen, Y.-J.;
Liu, L.; Wang, D.; Li, Ch.-J. AdV. Synth. Catal. 2005, 347, 1247.
(
5) Organic Synthesis in Water; Grieco, P. A., Ed.; Blackie Academic
&
Professional: London, 1998.
1
0.1021/jo0514568 CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/26/2006
J. Org. Chem. 2006, 71, 1317-1321
1317

Jankowska and Mlynarski
Mukaiyama-aldol reaction in aqueous ethanol.13 Recently, the
same group presented excellent example of hydroxymethylation
Successful application of zinc salt to asymmetric reaction in
aqueous solutions must rely on its possibly best fit into the chiral
ligand. Keeping in mind the well-known kinship of a zinc cation
with the nitrogen atom lonely electron pair, surpassing binding
14
of silicon enolates using scandium- and bismuth-based Lewis
acid.15
2+
21
The scope and limitation of this reaction is still, however,
not fully recognized, and attaining high enantioselectivity in
aldol reaction in aqueous media is generally not easy. Special
constants of Zn with water molecules, we found it reasonable
to test various types of N-binding ligands. Our initial studies
began with an evaluation of zinc complexes with ligands
containing one, two, and three nitrogen atoms. The enantiose-
lectivity of ligands was assessed in the catalytic aldol reaction
of propiophenone silyl enol ether 4 and benzaldehyde as
common substrates for the first stage optimization of the
1
2,13
ligands have to be chosen to obtain ee reaching 80%
and
diastereoselectivity in hitherto reported reactions is not excellent.
Finally, the elaborated methodologies failed in application to
aliphatic aldehydes for which a remarkable drop in the reaction
enantioselectivity was commonly observed.
To address all of these deficiencies and develop new
methodologies, we wish to report a novel chiral zinc catalyst
with pybox-type ligand for asymmetric Mukaiyama-aldol reac-
1
6
Mukaiyama process. Of the complexes surveyed, the
22
Zn(OTf)2-pybox catalysts with ligands 1-3 provided superior
levels of asymmetric inductions (Table 1).
When (S,S)-1 (22 mol %) and Zn(OTf) (20 mol %) were
2
1
6
2+
tion in aqueous media. Previously, synthetic Zn coordination
complexes have been studied extensively as simplified models
for various biological processes,17 e.g., aldol reactions catalyzed
used, the reaction between benzaldehyde and silyl enol ether 4
in THF/H O (9/1) at 0 °C gave the desired aldol adduct 6 in
2
good yield and good diastereo- and enantioselectivity (entry 1).
18
by type II aldolases, natural aldol reaction catalysts, containing
It is important to mention that the homogeneous reactions does
not need any stirring and the same yield and selectivity was
observed when the whole reaction mixture was alowed to stay
in the fridge at the appropriate temperature. Interestingly, similar
2+
Zn cofactor in the active site. The studies on aldol reactions
in aqueous media may serve to some extent as a model for
enzymatic processes in living organisms where water is a “life
solvent” because the same metal cofactor is responsible for the
substrate activation in both genuine enzymatic and laboratory
stereoselectivity was observed when THF/H O (1/1) was applied
2
as a solvent (entry 2). In this case, however, the yield dropped
1
7g
processes.
Here, we describe the detailed studies on our
probably because of limited contact between phases in the non-
homogeneous mixture. The same reaction in ethanol/water was
visibly faster but less enantioselective (entry 1 vs 3). From the
practical point of view, it was exciting to find out that the
reaction does not require a large excess of silyl enol ether and
1.2 equiv is sufficient to obtain reasonable yield.
catalyst and further improvements of the asymmetric aldol
reactions in aqueous media. Emphasis is placed on aliphatic
aldehydes, usually unsuitable substrates for such reactions.
Results and Discussion
N-Mono- and bidentate ligands were less promising sources
of chirality in tested reactions. This observation confirmed strong
Despite some promising examples of the direct aldol con-
densation promoted by chiral Zn-complexes, little is known
about zinc-supported Mukaiyama-aldol condensation in either
19
2
+
preferences of Zn toward formation of chiral complexes
stabilized by three nitrogen atoms in the aldol reactions in
aqueous media. This is a conspicuous analogy to type II
aldolases in which zinc ion is tightly coordinated by three
anhydrous or aqueous media. It was found previously that Lewis
acids based on Zn2+ were both stable and active in Mukaiyama
reaction in wet THF, although they gave moderate yields of
2
3
9
a
histidine residues in the reaction active site.
the aldol products. Planning our screening for an enantiose-
lective zinc-based catalyst for the reaction, we considered
published unpromising examples of enantioselective aldol
Application of ethanol instead of THF resulted in better
conversion yet affected enantioselectivity. Unlike wet THF, in
which Zn(OTf)2/1 was insoluble below -10 °C, application of
ethanol gave opportunity in lowering the reaction temperature.
Thus, at -20 °C both diastereo- and enantioselectivities of the
reaction improved noticeably, leading to 68% ee and 93% yield
reaction promoted by zinc triflate and chiral crown ether
combination,11 as well as spectacular results obtained by the
same group with asymmetric silyl enol ether based Mukaiyama-
Mannich-type reaction in aqueous media.20
(entry 7).
(
13) (a) Kobayashi, S.; Hamada, T.; Nagayama, S.; Manabe, K. Org.
The highest reaction enantioselectivity was observed when a
Lett. 2001, 3, 165. (b) Hamada, T. Manabe, K.; Ishikawa, S.; Nagayama,
S.; Shiro, M.; Kobayashi, S. J. Am. Chem. Soc. 2003, 125, 2989.
DME/water mixture was applied. In this case ee exceeded 80%,
but observed yield was unsatisfactory, even when 2 equiv of
enol ether 4 was engaged (entry 9). It was found that the addition
(
14) Ishikawa, S.; Hamada, T.; Manabe, K.; Kobayashi, S. J. Am. Chem.
Soc. 2004, 126, 12236.
15) Kobayashi, S.; Ogino, T.; Shimizu, H.; Ishikawa, S.; Hamada, T.;
Manabe, K. Org. Lett. 2005, 7, 4729.
16) For a preliminary report, see: Mlynarski, J.; Jankowska, J. AdV.
Synth. Catal. 2005, 347, 521.
13b
(
of 2,6-di-tert-butyl-4-methylpyridine was indifferent and did
not improve observed yield (entries 9 and 10).
(
(
17) (a) Lipscomb, W. N.; Str a¨ ter, N. Chem. ReV. 1996, 96, 2375. (b)
(20) (a) Kobayashi, S.; Hamada, T.; Manabe, K. J. Am. Chem. Soc. 2002,
124, 5640. (b) Hamada, T.; Manabe, K.; Kobayashi, S. Angew. Chem., Int.
Ed. 2003, 42, 3927. (c) Hamada, T.; Manabe, K.; Kobayashi, S. J. Am.
Chem. Soc. 2004, 126, 7768.
(21) Martel, A. E.; Smith, R. M. Critical Stability Constants; Plenum
Press: New York, 1974, 1975, 1977; Vols. 1-3.
(22) (a) Desimoni, G.; Faita, G.; Quadrelli, P. Chem. ReV. 2003, 103,
3119. (b) Iwasa, S.; Nakamura, H.; Nishiyama, H. Heterocycles 2000, 52,
939.
(23) (a) Belasco, J. G.; Knowles, J. R. Biochemistry 1983, 22, 122. (b)
Fessner, W. D.; Schneider, A.; Held, H.; Sinerius, G.; Walter, C.; Hixon,
M.; Schloss, J. V. Angew. Chem., Int. Ed. Engl. 1996, 35, 2219. (c) Dreyer,
M. K.; Schulz, G. E. J. Mol. Biol. 1996, 259, 458. (d) Dreyer, M. K.; Schulz,
G. E. J. Mol. Biol. 1993, 231, 549. (e) Kroemer, M.; Schulz, G. E. Acta
Crystallogr. 2002, D58, 824.
Wilcox, D. E. Chem. ReV. 1996, 96, 2435. (c) Molenveld, P.; Engbersen,
J. F. J.; Reindoudt, D. N. Chem. Soc. ReV. 2000, 29, 75. (d) Parkin, G.
Chem. ReV. 2004, 104, 699. (e) Aoki, S.; Kimura, E. Chem. ReV. 2004,
1
04, 769. (f) For a recent example, see: Jiang, H.; O’Neil, E. J.; DiVittorio,
K. M.; Smith, B. D. Org. Lett. 2005, 7, 3013. (g) Kofoed, J.; Reymond
J.-L.; Darbre, T. Org. Biomol. Chem. 2005, 3, 1850.
(
18) Fessner, W. D. In Modern Aldol Reactions; Mahrwald, R., Ed.;
Wiley-VCH: Weinheim, 2004; p 201.
19) (a) Kumagai, N.; Matsunaga, S.; Kinoshita, T.; Harada, S.; Okada,
S.; Sakamoto, S.; Yamaguchi, K.; Shibasaki, M. J. Am. Chem. Soc. 2003,
25, 2169. (b) Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000, 122, 12003.
(
1
(
(
b) Trost, B. M.; Ito, H.; Silcoff, E. R. J. Am. Chem. Soc. 2001, 123, 3367.
c) Trost, B. M.; Silcoff, E.; Ito, H. Org. Lett. 2001, 3, 2497. (d) Darbre,
T.; Machuqueiro, M. Chem. Commun. 2003, 1090.
1318 J. Org. Chem., Vol. 71, No. 4, 2006

Zn-Complex-Catalyzed Asymmetric Aldol Reactions
TABLE 1. Mukaiyama-Aldol Reaction of Silyl Enol Ether 4; Solvent Studies
a
c
L
catalyst mol %
solvent
temp (°C)
time (h)
yield (syn/anti)
ee (syn)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
1
2
3
1
1
1
1
1
1
1
1
1
1
20
20
20
20
20
20
20
20
20
20
20
20
10
5
THF-H2O(10%)
0
0
0
0
0
20
72
10
20
20
96
24
96
96
48
72
72
48
48
48
48
73 (9/1)
38 (93/7)
80 (9/1)
13 (7/3)
82
58 (S,S)
60 (S,S)
39 (S,S)
rac
24 (R,R)
13 (R,R)
68
76
82
79
75
THF-H2O(50%)
EtOH-H2O(10%)
CH2Cl2
THF-H2O(10%)
THF-H2O(10%)
0
56
EtOH-H2O(10%)
-20
-25
-25
-25
-25
-25
-25
-25
-25
-25
93 (96/4)b
52 (93/7)b
18 (92/8)b
DMF-H2O(10%)
DME-H2O(10%)
b,d
0
1
2
3
4
5
6
DME-H2O(10%)
18 (95/5)
THF/EtOH(1/1)-H2O(10%)
THF/EtOH(1/1)-H2O(10%)
THF/EtOH(1/1)-H2O(10%)
THF/EtOH(1/1)-H2O(10%)
DME/THF(1/1)-H2O(10%)
DME/EtOH(1/1)-H2O(10%)
43 (96/4)
84 (96/4)b
88 (94/6)b
84 (93/7)b
75
72
71
74
b
20
20
25 (92/8)
63 (94/6)b
78
a
Isolated yield. b 2.0 equiv of 4 was used. c ee values were determined on a Daicel Chiralpak AD-H column. d 100 mol % of 2,6-di-tert-butyl-4-
methylpyridine was admixed.
To find the optimal balance between the reaction yield and
stereoselectivity, we have tested mixed solvents. In the case of
wet ethanol/THF mixture (1:1) we obtained 84% yield when 2
equiv of 4 was used. Substrate loading did not affect observed
ee (entries 11 and 12). We were delighted to find that the
reaction proceeded in high yield with good enantioselectivity
even when 10 mol % of the catalyst was used (entry 13). In
general, 10 mol % of the catalyst delivered aldol products with
better yields; 5 mol % of the catalyst also worked well (entry
published results.10,12,13 This, as a rule, is in contrast with the
analogous reactions run under anhydrous conditions where the
anti-isomer is usually the major product.
2
,6a
We were delighted to find that the elaborated catalytic system
turned out to be highly diastereoselective (dr, 96/4, entry 12)
when compared to hitherto published examples. Diastereo-
isomeric ratios in previously presented reactions rarely exceeded
1
1,13
9/1 value and only for a narrow range of tested substrates.
10
Reported diastereoselectivities were modest for Cu(II) (3/1-
1
2
14) but when less than 20 mol % of the catalyst was used both
5/1) and Ga(III) (8/2-9/1) based catalysts.
stereoselectivity and enantioselectivity were, however, a little
lower. Aldol reaction conducted in DME-containing solvents
was still selective yet less efficient (entries 15 and 16).
The reaction in pure CH2Cl2 gave lower yield and dia-
stereoselectivity, and the product was found to be a racemate
The absolute configuration of the aldol product 6 resulted
from configuration of the ligand used. Thus (S,S)-1-pybox
produced aldol with (2S,3S)-configuration, whereas (R,R)-2 and
3
delivered the opposite enantiomer of 6. In all cases the absolute
configuration of the alcohol 6 was determined by comparison
(entry 4). The desired product 6 was not detected when dry
of the HPLC analysis and optical rotation value with literature
THF was used as reaction medium. Thus water plays an essential
role for attaining good yield and enantioselectivity in the
reaction. This observation encouraged us to take under consid-
eration the existence of water molecules in further stereochem-
ical discussion.
Next we checked the recyclability of the catalytic system
Zn(OTf)2-1. After the first cycle (ee 68%, Table 1, entry 7) the
active species was extracted to the water phase and concentrated.
We repeated the same reaction using EtOH/H2O (9/1) as a
solvent. The observed yield was high (98%), but selectivities
were dramatically decreased (ee 6%, de 46%). These results
suggested that although pybox ligand can be effectively recycled
as hydrophilic Zn-complex, some active intermediates were
extracted into the organic phase.
13b
data.
The stereochemical course of the reaction can be rationalized
by the model shown in Scheme 1. We assume that before an
aldehyde binding, the catalyst exists as an octahedral triaqua-
complex, as was proven during the investigation of bis(indanol)-
24
pybox with zinc triflate complex. To rationalize the observed
sense of induction, a complexation of the aldehyde to the zinc
ion to give a square pyramidal reacting complex is proposed.
This was previously shown for benzyloxyacetaldehyde with
25
26
Cu(pybox) and glyoxylate with Sc(pybox) complexes. In
both cases bidentate aldehydes occupied apical and equatorial
positions of the complex, replacing the vicinal triflates and the
water molecule. When an aldehyde coordinates to the Zn cation
In aqueous aldol reactions we observed a predominance of
syn-aldol products, which is in full agreement with previously
(
24) Jiang, M.; Dalgarno, S.; Kilner, C. A.; Halcrow, M. A.; Kee, T. P.
Polyhedron 2001, 20, 2151.
J. Org. Chem, Vol. 71, No. 4, 2006 1319

Jankowska and Mlynarski
SCHEME 1. Assumed Transition State Model in the
Asymmetric Aldol Reaction
TABLE 2. Examples of Zn(OTf)2(pybox-1)-Catalyzed
Mukaiyama-Aldol Reactions
complexed with (S,S)-pybox 1, in the fashion shown in Scheme
1
, the re face of the coordinated aldehyde carbonyl is shielded
by the isopropyl substituent of 1, allowing nucleophilic attack
of silyl enol ether predominantly from the si face. It is possible
that the water molecule coordinated to the zinc cation can
additionally fix this structure by hydrogen bond formation or
steric crowding. Such a structure with tridentate ligands was
observed when urea and two molecules of water coordinate to
27
the zinc cation. The (2S,3S)-adduct is considered to be formed
selectively in this manner.
In an effort to expand the scope of the zinc-promoted
Mukaiyama aldol process, various aldehydes and other silyl enol
ethers were then examined, and the results are summarized in
Tables 2 and 3.
Not only aromatic aldehydes (Table 2, entries 1-5) but also
R,â-unsaturated, e.g., cinamaldehyde (entry 6), and aliphatic
substrates (entries 7-14) gave good yields as well as stereo-
selectivity. In most cases observed stereoselectivity was high
and surpassing (9/1) diastereomers ratio when 20 mol % of the
catalyst was used. Its higher values were characteristic for
o-substituted aldehydes, for instance, (98/2) for 2-chlorbenz-
aldehyde (entry 4), and reached the top for o-anisaldehyde, for
which the anti-aldol was not observed in the reaction mixture
(
entry 2). Moreover, hindered o-anisaldehyde was more reactive
as compared to its para counterpart, probably because of
interaction of the methoxy function with the metal core of the
catalyst.
a
ee values were determined on a Daicel Chiralpak AD-H column.
Reaction temperature 0 °C. c Reaction temperature -10 °C.
b
Diminishing the catalyst loading to 10 mol % did not affect
reaction yield but decreased diastereoselectivity (entries 1-5).
We did not observe, however, correlation between the
enantioselectivity of an Mukaiyama-aldol reaction and the nature
of the para-substituent of a benzaldehyde substrate. Although
usually increasing ee with increasing electron-donating character
of the substituent was observed for a metal-catalyzed addition
obviously less reactive, leading however to the desired product
at 0 °C with the loss of reaction enantioselectivity. Heptanal
despite slightly lower reactivity showed the same level of
stereoselectivity as aromatic aldehydes (entry 9). For aliphatic
aldehydes special conditions have to be applied because of lower
substrate reactivity. In aqueous ethanol, hydrolysis of enol ether
4 was faster than the desired addition and low yield was
observed. We solved this problem by application of medium
composed of wet THF with 20 vol % of EtOH at -10 °C (entry
29
to carbonyl group, it was not previously observed in aqueous
Mukaiyama reaction.1
2,13
We were delighted to find out that the elaborated catalytic
system can be successfully applied for aliphatic aldehydes
without significant loss of diastereo- and enantioselectivity of
the aldol coupling process (entries 7-12). Pivalaldehyde was
9
). Under the elaborated conditions heptanal, butanal, and
phenylpropanal provided aldols 7i-k in acceptable yields and
good levels of stereocentrol. Retention of the good level of ee
in the reaction with aliphatic aldehyde is a valuable observation
as the application of the most previously demonstrated catalytic
systems resulted in lower stereosectivity with those important
substrates.
(
25) Evans, D. A.; Kozlowski, M. C.; Murry, J. A.; Burgey, C. S.;
Campos, K. R.; Connell, B. T.; Staples, R. J. J. Am. Chem. Soc. 1999, 121,
69.
26) Evans, D. A.; Sweeney, Z. K.; Rovis, T.; Tedrow, J. S. J. Am. Chem.
Soc. 2001, 123, 12095.
27) Komen, R. P.; Miskelly, G. M.; Oliver, A.; Rickard, C. E. P. Acta
Crystallogr., Sect. C 1999, 55, 1213.
6
(
(
Benzyloxyacetaldehyde was reactive only at 0 °C, which
resulted in only a moderate level of ee (entry 12). Initial studies
on ethyl glyoxalate showed that this important substrate2
delivered product in good yield but with low stereoselection
(
(
28) Evans, D. A.; Messe, C. E.; Wu, J. Org. Lett. 2002, 4, 3375.
29) Yokomatsu, T.; Yamagishi, T.; Shibuya, S. Tetrahedron: Asymmetry
6,28
1
993, 4, 1783.
1320 J. Org. Chem., Vol. 71, No. 4, 2006

Zn-Complex-Catalyzed Asymmetric Aldol Reactions
TABLE 3. Mukaiyama-Aldol Condensation of Acetophenone and
Cyclohexanone Silyl Enol Ethers
the same rules were observed, favoring o-substituted aldehydes.
For example, o-anisaldehyde was a far more reactive and
selective substrate when compared to p-anisaldehyde (entry 6
vs 7).
Silyl enol ethers 9 and 10 derived from 3-pentanone and
cyclohexanone, respectively, were not good substrates in the
present catalytic system (entries 8-10). While reaction with
enol ether 9 afforded the aldol product in racemic form, the
cyclohexanone derivative 10 led to formation of syn-aldol in
1
0% ee (entry 10) and anti-aldol in 40% ee.
In summary, we have developed Zn(OTf)2-pybox as an
efficient chiral catalyst for asymmetric Mukaiyama-aldol con-
densation in aqueous media. Under the elaborated conditions
the reaction of aldehydes and silyl enol ethers proceeds with
good to high yields and stereoselectivity. High enantioselectivity
in the aldol reaction in aqueous media is difficult to achieve,
but compared to hitherto reported reactions the selectivity is
good, and readily available combination of Lewis acid and chiral
ligand demonstrate practical utility of presented catalytic system.
Newly elaborated catalyst allows to increase the water content
in the reaction mixture up to 50% what would have important
advantages to environmental issues.
Experimental Section
General Methods. Reactions were controlled using TLC on
silica alu-plates (0.2 mm). All reagents and solvents were purified
and dried according to common methods. All organic solutions were
2 4
dried over Na SO . Reaction products were purified by flash
chromatography using silicagel 60 (240-400 mesh). Diastereomeric
1
ratio was detected using H NMR technique. Enantiomer ratios were
measured using chiral HPLC columns (Chiralpak AS-H and AD-
H) with hexane/2-propanol solvent gradient.
Typical Procedure for Asymmetric Aldol Reactions. To a
solution of pybox ligand 1 (37 mg, 0.125 mmol) and zinc
trifluoromethanesulfonate (36 mg, 0.10 mmol) in 1.5 mL of THF/
a
b
Isolated yield. ee values were determined on a Daicel Chiralpak AS
c
column. E/Z ) 7/3.
EtOH(1/1)-H O(10%) at -25 °C were added silyl enol ether 4
2
(
entry 13). Application of aqueous formaldehyde was unsuc-
(250 µL, 1 mmol, 2 equiv) and the appropriate aldehyde (0.5 mmol).
The reaction mixture was stirred for 20 min at the same temperature,
and then the homogeneous solution was left standing in the fridge
at the appropriate temperature for 10-168 h. The reaction was
diluted with MTBE and washed with water and brine. Organic
solution was dried and evaporated to dryness, and the residue was
purified by silica gel chromatography (AcOEt/hexane, 1/4).
cessful (entry 14).
Experiments to probe the scope of the enol ether substrates
are summarized in Table 3. First, the reactivity of acethophenone
surrogate 8 was investigated. Such a variant of Mukaiyama-
type reaction is problematic because of a stronger tendency
toward hydrolysis affecting reaction yield. Again, we tested the
combination of all three pybox ligands 1-3 with zinc triflate.
Because of the much less reactivity of substrate, the best results
were obtained with as much as 3 equiv of 8 at 0 °C when THF/
H2O was used as a medium. In ethanol-based solvent we
observed faster hydrolysis of the enol ether substrate. Surpris-
ingly, for condensation of 8 the most promising source of
chirality turned out to be hm-pybox 22 (Table 3, entry 2).
The absolute configuration of the alcohol 11a was determined
Acknowledgment. We thank the Alexander von Humboldt
Foundation for generous donation of the HPLC system.
Supporting Information Available: Characterization data of
the aldol adducts. This material is available free of charge via the
Internet at http://pubs.acs.org.
2b
JO0514568
3
0
by comparison of the optical rotation with literature data.
In the case of the condensation of 8 with aromatic aldehydes
(30) Mashraqui, S. H.; Kellogg, R. M. J. Org. Chem. 1984, 49, 2513.
J. Org. Chem, Vol. 71, No. 4, 2006 1321