Iron(II) and zinc(II) complexes with designed pybox ligand for asymmetric aqueous Mukaiyama-aldol reactions

Article abstract of DOI:10.1021/jo0621470

An iron(II) complex with a hindered hydroxyethyl-pybox (he-pybox) ligand shows improved catalytic activity and enantioselectivity for asymmetric Mukaiyama-aldol reactions in aqueous media. This water-stable chiral Lewis acid promotes condensation of aroma

Full text of DOI:10.1021/jo0621470

TABLE 1. Mukaiyama-Aldol Reaction Catalyzed by FeII Salt:
Effect of Solvents and Ligands
Iron(II) and Zinc(II) Complexes with Designed
pybox Ligand for Asymmetric Aqueous
Mukaiyama-Aldol Reactions
Joanna Jankowska, Joanna Paradowska, Bartosz Rakiel,
and Jacek Mlynarski*
Institute of Organic Chemistry, Polish Academy of Sciences,
Kasprzaka 44/52, 01-224 Warsaw, Poland
mlynar@icho.edu.pl
ReceiVed October 17, 2006
entry
solvent
ligand yield (%)a (syn/anti) ee syn (%)b
1
2
3
4
5
6
7
8
9
EtOH-H2O(10%)
EtOH-H2O(20%)
EtOH
EtOH-H2O(10%)
EtOH-H2O(20%)
EtOH-H2O(10%)
EtOH-H2O(10%)
EtOH-H2O(10%)
EtOH-H2O(10%)
1
1
1
2a
2a
3a
2b
3b
4d
63 (93/7)
60 (95/5)
30 (81/19)
70 (91/9)
65 (85/15)
65 (9/1)
62 (96/4)
75 (92/8)
82 (92/8)
40 (S,S)c
62 (S,S)
40 (S,S)
68 (R,R)
58 (R,R)
27 (S,S)
38 (R,R)
70 (S,S)
rac
a Isolated yield after silica gel chromatography. b Determined by HPLC
analysis using Chiralpak AD-H column. c The absolute configuration of the
enol 7a was determined by comparison of the HPLC analysis with literature
data in ref 9. d Ph-pybox.
An iron(II) complex with a hindered hydroxyethyl-pybox (he-
pybox) ligand shows improved catalytic activity and enan-
tioselectivity for asymmetric Mukaiyama-aldol reactions in
aqueous media. This water-stable chiral Lewis acid promotes
condensation of aromatic silyl enol ethers with a range of
aldehydes with good yields, excellent syn-diastereoselectivity
and up to 92% ee. The combination of the same ligand with
ZnII salt is also demonstrated as a remarkably efficient and
water-compatible chiral Lewis acid.
The synthesis of enantiopure molecules via aldol-type reac-
tions constitutes another interesting problem,4 and the develop-
ment of efficient aldol methods in aqueous solvents is an
intensively investigated topic nowadays.5 The Mukaiyama-aldol
reaction in aqueous media has also been a subject of current
importance.6 Only a few catalysts containing copper,7 lead,8
praseodymium,9 or gallium10 have been used in their enanti-
oselective variants. Recently, excellent examples of the hy-
droxymethylation of silicon enolates using scandium-11 and
bismuth-based12 Lewis acids have been reported.
The scope and limitation of this reaction is still, however,
not fully recognized. Attaining high enantioselectivity in aldol
Organic reactions in which water is used as a solvent or
cosolvent have attracted a great deal of attention recently
because of the unique properties of water and its key role as a
solvent for green chemistry.1 Although various kinds of reactions
have been developed in aqueous solvents recently,2 asymmetric
catalysis promoted by chiral Lewis acids in such media is still
at an initial stage mostly because of the water incompatibility
of known catalysts.3 Moreover, enantioselective versions of
Lewis acid mediated reactions in aqueous solvents are difficult
to achieve because competitive ligand exchange between a chiral
ligand and water molecules easily occurs, and this affects
enantioselectivity.
(4) (a) Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH:
Weinheim, 2004. (b) Machajewski, T. D.; Wong, C.-H. Angew. Chem., Int.
Ed. 2000, 39, 1352.. (c) Palomo, C.; Oiarbide, M.; Garcia, J. M. Chem.
Soc. ReV. 2004, 33, 65.
(5) (a) Fernandez-Lopez, R.; Kofoed, J.; Machuqueiro, M.; Darbre, T.
Eur. J. Org. Chem. 2005, 5268. (b) Hayashi, Y.; Sumiya, T.; Takahashi,
J.; Gotoh, H.; Urushima, T.; Shoji, M. Angew. Chem., Int. Ed. 2006, 45,
958. (c) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Tanaka, F.;
Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128, 734.
(6) (a) Kobayashi, S.; Hachiya, I. J. Org. Chem. 1994, 59, 3590. (b)
Kobayashi, S.; Nagayama, S.; Busujima, T. J. Am. Chem. Soc. 1998, 120,
8287. (c) Mun˜oz-Mun˜iz, O.; Quintanar-Audelo, M.; Juaristi, E. J. Org.
Chem. 2003, 68, 1622.
(7) Kobayashi, S.; Nagayama, S.; Busujima, T. Tetrahedron 1999, 55,
8739.
(8) Nagayama, S.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 11531.
(9) Hamada, T. Manabe, K.; Ishikawa, S.; Nagayama, S.; Shiro, M.;
Kobayashi, S. J. Am. Chem. Soc. 2003, 125, 2989.
(10) 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.
(11) Ishikawa, S.; Hamada, T.; Manabe, K.; Kobayashi, S. J. Am. Chem.
Soc. 2004, 126, 12236.
(1) Organic Synthesis in Water; Grieco, P. A., Ed.; Blackie Academic
& Professional: London, 1998. (b) Li, Ch.-J.; Chan, T.-H. Organic
Reactions in Aqueous Media; John Wiley & Sons: New York, 1997.
(2) (a) Lindstro¨m, U. M. Chem. ReV. 2002, 102, 2751. (b) Sinou, D.
AdV. Synth. Catal. 2002, 344, 221. (c) Lindstro¨m, U. M.; Andersson, F.
Angew. Chem., Int. Ed. 2006, 45, 548. (d) Pirrung, M. C. Chem. Eur. J.
2006, 12, 1312.; (e) Li, Ch.-J.; Chen, L. Chem. Soc. ReV. 2006, 35, 68.
(3) (a) Manabe, K., Kobayashi, S. Chem. Eur. J. 2002, 8, 4095. (b)
Kobayashi, S.; Manabe, K. Acc. Chem. Res. 2002, 35, 209. (c) Kobayashi,
S.; Ogawa, C. Chem. Eur. J. 2006, 12, 5954.
(12) Kobayashi, S.; Ogino, T.; Shimizu, H.; Ishikawa, S.; Hamada, T.;
Manabe, K. Org. Lett. 2005, 7, 4729.
10.1021/jo0621470 CCC: $37.00 © 2007 American Chemical Society
Published on Web 02/22/2007
2228
J. Org. Chem. 2007, 72, 2228-2231

TABLE 2. Effect of Metal Salt on Reaction Yield and Selectivity
TABLE 3. Examples of FeII-3c-Catalyzed Mukaiyama-Aldol
Reactions
entry
MeXn
yield (%)a (syn/anti)
ee syn (%)b
1
2
3
4
5
6
7
8
9
10
Zn(OTf)2
Zn(OTf)2
Cu(OTf)2
In(OTf)3
Pr(OTf)3
Bi(OTf)3
NiCl2
RuCl2
CeCl3
FeCl2
84 (92/8)
84 (94/6)
17 (82/18)
78 (95/5)
84 (65/35)
40 (95/5)
trace
trace
67 (65/35)
75 (95/5)
68 (2S,3S)
62c
13
rac
34
9
30
72
a Isolated yield after silica gel chromatography. b Determined by HPLC
analysis using Chiralpak AD-H column. c pybox 1 was used instead of 3b.13
reactions in aqueous media is generally not easy, and diaste-
reoselectivity in hitherto reported reactions is not excellent.
Moreover, most reported catalysts are composed of heavy or
rare earth metals, which creates some drawbacks for their
applications because of toxicity or high price. To address this
issue, we have recently discovered zinc-13 and iron-based14 chiral
Lewis acids as cheap, nontoxic, and environmentally benign
catalysts for the asymmetric Mukaiyama carbon-carbon bond-
forming process.
Application of iron-based chiral Lewis acids to asymmetric
synthesis seems to be particularly exciting as iron is one of the
most abundant metals on earth and consequently one of the
cheapest and most environmentally acceptable. Interest in well-
defined iron complexes as catalysts for bond-forming reactions
is an area of ongoing development.15
Our group recently reported the first example of water-
compatible iron-based chiral Lewis acids for the Mukaiyama
reaction.14 We showed that application of iron complexes with
convenient chiral ligands is possible yet problematic because
of some instability of iron complexes in aqueous media.
Moreover, the catalytic system was capricious and very sensitive
to many reaction factors. Thus, reproducibility of the reaction
was far more problematic when compared to other known
catalysts. Finally, the enantioselectivity of the catalyst left room
for further improvement.
Herein we describe studies on the application of an iron
complex composed of iron(II) chloride and tuned, lipophilic
pybox ligand as stable, efficient, and reliable iron-based chiral
Lewis acids for aqueous asymmetric Mukaiyama-aldol reactions.
Our initial aim was to identify the best-suited chiral ligand
in terms of both reaction conversion and enantioselection. At
first, Z-silyl enol ether 5 was reacted with benzaldehyde in
a Isolated yield after silica gel chromatography. b Determined by HPLC
analysis using Chiralpak AD-H and AS-H columns. c Carried out in
anhydrous ethanol.
aqueous ethanol in the presence of iron(II) chloride and various
pybox ligands. The results are summarized in Table 1.
A series of modified pybox ligands was evaluated in associa-
tion with FeCl2 to identify the most enantioselective and reliable
system. Although in all cases the reaction proceeded smoothly
to give the aldol product 7a in good yields and diastereoselec-
tivities, the enantioselectivities depend on the structure of pybox
ligands. In a deoxygenated aqueous system, commercial pybox
116 provides aldol 7a in up to 62% ee. Application of
hydroxymethyl-pybox 2a17 slightly increased the ee (68%), while
its hydroxyethyl analogue 3a resulted in decreased selectivity
(27%). Further, we decided to test more hindered analogues of
2a and 3a. Whereas protection of the hydroxymethyl-pybox by
(13) Jankowska, J.; Mlynarski, J. J. Org. Chem. 2006, 71, 1317.
(14) Jankowska, J.; Paradowska, J.; Mlynarski, J. Tetrahedron Lett. 2006,
47, 5281.
(15) Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem. ReV. 2004, 104,
6217.
(16) Desimoni, G.; Faita, G.; Quadrelli, P. Chem. ReV. 2003, 103, 3119.
J. Org. Chem, Vol. 72, No. 6, 2007 2229

TABLE 4. Examples of ZnII-3c-Catalyzed Mukaiyama-Aldol Reactions
a Isolated yield after silica gel chromatography. b Determined by HPLC analysis using Chiralpak AD-H and AS-H columns.
O-tert-butyldimethylsilyl group17b did not improve the selectivity
and even resulted in a drop of enantioselectivity (38%),
application of the TBS-hydroxyethyl-pybox 3b17c increased
selectivity as reflected in the higher ee (70%).
Subsequently, various metal salts were examined in the
asymmetric aldol reaction using the best ligand so far, 3b (Table
2). We screened some water-compatible Lewis acids as potential
catalysts for the Mukaiyama-aldol reaction. Although almost
all salts that were studied catalyzed the formation of 7a in good
yield, the complexes derived from Zn(OTf)2 and FeCl2 afforded
substantially higher enantioselectivity. Only for an iron salt,
application of deoxygenated solvents was necessary because of
an unwelcome tendency toward oxidation of the Fe(II) to Fe-
(III), which catalyzes the reaction but produces racemates.
As can be seen from the previous study, the readily available
combination of hindered hydroxyethyl-pybox 3b and iron(II)
chloride turned out to be the most selective couple in the
aqueous asymmetric Mukaiyama-aldol reaction. These consid-
erations led us to prepare a new, designed analogue. We decided
to test a more hindered and lipophilic pybox family member.
We assumed that more bulky ligand substituents can effectively
shield one of the sites of nucleophilic attack, resulting in the
higher enantioselectivity. On the other hand, recent findings
suggest that selective hydrophobic acceleration can play an
interesting and important part in organic synthesis in water.2c
Thus, we decided to equip hydroxyethyl-pybox with bulky and
lipophilic substituents. Using a modified literature procedure17c
we prepared O-tert-butyldiphenylsilyl-hydroxyethyl-pybox (TPS-
he-pybox) 3c.18
(17) (a) Iwasa, S.; Nakamura, H.; Nishiyama, H. Heterocycles 2000, 52,
939. (b) Iwasa, S.; Tsushima, S.; Shimada, T.; Nishiyama, H. Tetrahedron
2002, 58, 227. (c) Iwasa, S.; Tsushima, S.; Nishiyama, K.; Tsuchiya, Y.;
Takezawa, F.; Nishiyama, H. Tetrahedron: Asymmetry 2003, 14, 855.
(18) For the synthesis of 3c from (2S,3R)-L-threonine methyl ester
hydrochloride and pyridinedicarbonyldichloride, see Supporting Information.
2230 J. Org. Chem., Vol. 72, No. 6, 2007

The enantioselectivity of this ligand was assessed in the
catalytic aldol reaction of 5. As expected, the more bulky
substituents had a profound effect on enantioselectivity (Table
3, entry 1). Aqueous ethanol proved to be the optimal solvent,
providing aldol product in 84% yield and 84% ee at 0 °C.
The generality of the reaction was examined in detail using
10 mol % of the catalyst, and the results are summarized in
Table 3. The Mukaiyama-type reactions proceeded well using
various substrates. The reaction has broad applicability with
respect to the aldehyde. Both good enantioselectivity (70-90%)
and excellent syn-selectivity were obtained when silyl enol ether
5 and aromatic aldehydes were employed. Heteroaromatic
2-pyridinecarboxyaldehyde delivered racemates (entry 8). Al-
though the aldol reaction of R,â-unsaturated (entry 9) and
aliphatic (entry 10) substrates proceeded in aqueous solvent,
the enantioselectivity was moderate. For all reactions catalyzed
by Fe(II) complexes, deoxygenated solvents were used. In the
case of the complex composed of Fe(II) with 3c, the resulting
species was far more stable under the reaction conditions when
compared to previously elaborated systems.14 As a result the
catalyst was observed to be more convenient and reliable. This
resulted in better reproducibility of the reaction yield and ee.
To explain this tendency, we assume that bulky silyl groups in
the ligand better shield the central iron cation, which suppress
the Fe(II) to Fe(II) oxidation process.
The catalytic utility and flexibility of ligand 3c was demon-
strated as well in the reaction promoted by ZnII salt. To our
delight this zinc-based chiral Lewis acid showed high activity
in aqueous Mukaiyama-aldol reactions. Thus, the selectivity of
the process was improved by replacing commercial ligand 113
with TPS-he-pybox 3c. Moreover, zinc catalyst seems to be the
more convenient for such reaction as this complex is not air-
sensitive.
Several examples of the catalytic asymmetric aldol reactions
of silyl enol ether 5 with aldehydes are shown in Table 4. The
best solvent for a range of aldehydes was ethanol-water. In
general, the amount of water did not affect selectivity. However,
the catalyst used is not applicable to solvents with more than
25% water because of solubility problems. A good level of ee,
reaching 90%, was maintained for aromatic (entries 1-5), R,â-
unsaturated (entry 6), and aliphatic aldehydes (entry 7).
Despite the bulky substituent in ligand 3c, the same geometry
of the resulting complex can be postulated as it was observed
for other metal-pybox complexes.16 Zinc ion coordinates to three
nitrogen atoms (in the planar geometry) resulting in the
octahedral structure of the whole complex where octahedron
positions are held by water molecules.19 Due to the bulky silyl
group the attack toward the coordinated carbonyl group is more
effectively shielded from the one face. As a result the higher
enantioselectivity of the reaction was observed when compared
to the same process catalyzed by zinc complex with less
hindered pybox ligands.13
In summary, the application of the iron(II)-pybox complexes
as reliable and water-compatible chiral Lewis acids for the
Mukaiyama-aldol reactions has been accomplished. The use of
10% of this chiral catalyst allowed better reactivity and
enantioselectivity than with commercial ligands. Moreover, the
stability of the catalytic system is far more satisfactory when
compared to previously described iron(II) catalysts. An easy-
to-prepare pybox-type ligand showed high selectivity in the
reaction catalyzed by both FeII and ZnII chiral Lewis acids. The
developed zinc-based chiral Lewis acid seems to be the most
efficient and enantioselective catalyst for the aqueous Mu-
kaiyama condensation.20
Experimental Section
General Procedure for Asymmetric Aldol Reactions Cata-
lyzed by FeII Salt. A mixture of TPS-he-pybox (3c) (47 mg, 0.06
mmol, 12 mol %) and iron(II) chloride (6.5 mg, 0.05 mmol, 10
mol %) in 1.5 mL of deoxygenated EtOH/H2O (9/1) was stirred at
0 °C under Ar until all solid was observed to dissolve (15-20 min).
To the resulting deep-red solution were added silyl enol ether 5
(230 µL, 1.0 mmol, 2 equiv) and the appropriate aldehyde (0.5
mmol), and resulting solution was stirred at 0 °C for 5 h under Ar.
The reaction was diluted with MTBE and washed with water and
brine. The organic phase was dried and evaporated to dryness, and
the residue was purified by silica gel chromatography (typically,
AcOEt/hexane, 1:4).
General Procedure for Asymmetric Aldol Reactions Cata-
lyzed by ZnII Salt. A mixture of TPS-he-pybox (3c) (23 mg, 0.03
mmol, 12 mol %) and zinc(II) trifluoromethanesulfonate (9 mg,
0.025 mmol, 10 mol %) in 1 mL of EtOH/H2O (9/1) was stirred at
-20 °C (15-20 min). To the resulting homogeneous solution were
added silyl enol ether 5 (115 µL, 0.5 mmol, 2 equiv) and the
appropriate aldehyde (0.25 mmol), and resulting homogeneous
solution was left in the refrigerator at -20 °C overnight without
stirring. The reaction mixture was poured onto a silica gel column
and eluted by AcOEt/hexane (1:4) to yield the desired aldols.
Supporting Information Available: General experimental
procedure for FeII- and ZnII-based catalysts, full characterization
of compounds 7a-k, and synthesis of ligand 3c. This material is
available free of charge via the Internet at http://pubs.acs.org.
(19) Jiang, M.; Dalgarno, S.; Kilner, C. A.; Halcrow, M. A.; Kee, T. P.
Polyhydron 2001, 20, 2151.
(20) For comparison see the following. Reference 9: 7a 90% yield, 78%
ee; 7b 91% yield, 75% ee; 7i 77% yield, 76% ee; 7j 53% yield, 47% ee.
Reference 10: 7a 85% yield, 85% ee; 7b 80% yield, 84% ee; 7i 90% yield,
86% ee. Reference 13: 7j 55% yield, 72% ee.
JO0621470
J. Org. Chem, Vol. 72, No. 6, 2007 2231