Enantioselective reduction of aromatic and aliphatic ketones catalyzed by ruthenium complexes attached to β-cyclodextrin

Article abstract of DOI:10.1002/anie.200460102

Water-soluble chiral Ru complexes with a β-cyclodextrin unit have been shown to catalyze the reduction of aliphatic ketones (see scheme) with up to 97% ee and in good to excellent yields in the presence of sodium formate. The β-cyclodextrin unit is an essential component of the catalyst. It contributes to the unprecedented levels of enantioselectivity observed through the preorganization of the substrates in the hydrophobic cavity.

Full text of DOI:10.1002/anie.200460102

Angewandte
Chemie
Asymmetric Reduction
Enantioselective Reduction of Aromatic and
Aliphatic Ketones Catalyzed by Ruthenium
Complexes Attached to b-Cyclodextrin**
Alain Schlatter, Mrinal K. Kundu, and Wolf-D. Woggon*
Molecular recognition of substrates by cyclodextrins is made
possible by noncovalent interactions in the hydrophobic
cavity of the water-soluble, cyclic sugar oligomers. Inclusion
complexes of cyclodextrins[1] and their reactions constitute
one of the earliest examples of supramolecular chemistry.[2]
As a result of these unique features, cyclodextrins can be used
to mediate regioselective reactions[3] and in particular for
preparing enzyme models.[4,5]
In this context, the binding properties of b-cyclodextrins
have been complemented with chemically reactive subunits,
[*] A. Schlatter, Dr. M. K. Kundu, Prof. W.-D. Woggon
Department of Chemistry
Universityof Basel
St. Johanns-Ring 19, 4056 Basel (Switzerland)
Fax: (+41)61-267-1102
E-mail: wolf-d.woggon@unibas.ch
[**] We thank the Swiss National Science Foundation and the Roche
Foundation for supporting this research. Markus Neuburger is
gratefully acknowledged for X-ray crystallographic analysis.
Angew. Chem. Int. Ed. 2004, 43, 6731 –6734
DOI: 10.1002/anie.200460102
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6731

Communications
either by attaching functional groups such as acid–base
as the only chiral unit of the Ru complex the alcohol products
are formed with remarkable enantioselectivity, predomi-
nantly with the R configuration (Table 1). Evidently the
observed ee values correlate with the binding constants of
the ketones to b-cyclodextrin,[1] thus reflecting the preorga-
nization of substrates such that Si addition of the hydride to
the carbonyl group is preferred in the reactive complex.[11]
catalysts[3] or by linking b-cyclodextrins to metal com-
plexes.[4,5] In most cases superb reactivity and a very high
degree of regioselectivity were observed. In contrast, enan-
tioselective reactions with b-cyclodextrin (b-CD) as the only
chiral subunit of the catalyst in general gave products with
ee values well below 50%. For example, the highest enantio-
meric excess reported for a product of NaBH4 reduction of an
aromatic ketone in the presence of b-cyclodextrin was
Table 1: Enantioselective reduction of ketones 7–11 with the catalyst 2+4
(10 mol%).
[8]
24% ee.[6] Additives, such as amines[7] or aminoboranes,
improved the enantioselectivity, but only at the expense of the
yield. We report herein our results on the first ruthenium–
arene complexes of b-cyclodextrin-modified amino alcohols
and their use in asymmetric hydrogenation reactions of
prochiral ketones.
Ketone
R1
R2
Alcohol[a]
Yield [%][b]
ee [%][c]
7
8
9
10
11
H
H
p-CH3
p-Cl
p-tBu
CH3
C2H5
CH3
CH3
CH3
(R)-12
(R)-13
(R)-14
(R)-15
(R)-16
81
61
67
93
64
12
6
31
47
47
Mono(O-6-tosyl)-b-cyclodextrin (1, b-CD-Tos) is com-
mercially available and can also be prepared by the tosylation
of b-CD on a large scale.[9] The amino alcohol linked b-
cyclodextrins 2 and 3 were obtained in good yields as
crystalline compounds by the treatment of 1 with an excess
of the amino alcohol. [{RuCl2(C6H6)}2] (4) was prepared by a
literature procedure.[10] The formation of Ru complexes of 2
[a] Absolute configuration based on optical rotation. [b] Yields based on
GLC analysis and isolated material. [c] Enantiomeric excess determined
by 1H NMR spectroscopy(Eu(tfc)
) (tfc=3-(trifluoromethylhydroxy-
3
methylene)-d-camphorate) and HPLC analysis (chiracel OD-H).
1
and 3 (Scheme 1) was shown to be quantitative by H NMR
Since it is known from work by other research groups[12]
that asymmetric reduction catalyzed by Ru/amino alcohol
complexes lacking a cyclodextrin unit is largely dependent on
the chirality at the carbinol carbon atom (C2), we prepared 3
by the condensation of (S)-(+)-1-amino-2-propanol and b-
CD-Tos (1). Ligand 3 was isolated in 66% yield as a white
solid and was subsequently characterized by high-field NMR
spectroscopy, MS(ESI), and X-ray crystal-structure analysis
(Figure 1). Initial experiments with the Ru complex of 3
Scheme 1. Synthesis of Ru complexes of the amino alcohol b-cyclodextrins 2 and
3. The structures of 5 and 6 are tentativelyassigned.
spectroscopic studies (600 MHz, D2O). For example, signifi-
cant chemical-shift changes are observed between 2 and 5:
The doublets assigned to the two H atoms at C6’ of 2 shift
downfield by 0.56 ppm, and the triplet assigned to the
H atoms at C1 of 2 shifts downfield by 0.49 ppm. The
formation of the Ru complex 6 from 3 leads to the following
chemical-shift changes: The signals for the two H atoms at C6’
shift downfield by 0.56 ppm and 0.51 ppm, and those for the
H atoms at C1 shift downfield by 0.36 ppm and 0.54 ppm.
For catalytic reactions, the Ru complexes were formed in
situ and treated with ketones at room temperature under an
argon atmosphere in the presence of excess sodium formate
as the hydrogen source (Scheme 2). Even with b-cyclodextrin
Figure 1. Structure of ligand 3 derived from X-raycrystal-structure
analysis.
revealed a solubility problem in water. To avoid rather dilute
conditions the transfer-hydrogenation reactions with 3 were
carried out in a mixture of H2O/DMF (3:1; see Experimental
Section; DMF = N,N-dimethylformamide).
When the b-CD derivative 3 was used, the products were
obtained with ee values of up to 97% and in acceptable yields
(Table 2). It is interesting to note that with 3 as a ligand for
Ru, acetophenone (7) was reduced to (S)-12 with 77% ee; in
Scheme 2. Asymmetric reduction of ketones in water.
6732
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Chemie
Table 2: Enantioselective reduction of ketones 7–11 with the catalyst
3+4 (10 mol%).
Ketone
R1
R2
Alcohol[a]
Yield [%][b]
ee [%][c]
7
8
9
10
11
H
H
p-CH3
p-Cl
p-tBu
CH3
C2H5
CH3
CH3
CH3
(S)-12
(S)-13
(S)-14
(S)-15
(S)-16
90
63
69
77
51
77
80
94
87
97
[a], [b], and [c]: see Table 1.
contrast, the Ru complex of (S)-1-amino-2-propanol lacking
the b-cyclodextrin unit gave 12 in only ꢀ 50% ee in favor of
the S isomer.[13] Since we obtained R alcohols by using Ru
complexes with ligand 2 and S alcohols with ligand 3 our
results suggest a clear dominance of the chirality at C2 on the
enantioselectivity.
The catalytic system described herein also enables the
synthesis of 2H-enriched benzyl alcohols starting from
ketones and with sodium [D1]formate as a deuterium source
for isotope labeling. Thus, ketones 7, 8, and 10 were reduced
with 10% of 3+4 and DCO2Na (98% D) in a H2O/DMF
mixture (3:1, 500 mL) to give S deuterated alcohols 17, 18, and
19 in good yields and with enantioselectivities comparable to
those observed with HCOONa. High-field NMR (600 MHz)
2
spectroscopic measurements showed that H-labeling was as
high as > 97 atom% (Table 3).
Table 3: Enantioselective reduction of ketones 7, 8, and 10 with the
catalyst 3+4 (10 mol%) and DCO2Na.
Ketone
R1
R2
Alcohol[a]
Yield [%][b]
ee [%][c]
7
8
10
H
H
p-Cl
CH3
C2H5
CH3
(S)-17
(S)-18
(S)-19
79
53
70
77
76
87
[a], [b], and [c]: see Table 1.
Further examples demonstrate the potential scope of the
system. a-Ketoesters, such as 20, are reduced quantitatively to
the corresponding R-configured alcohols 21 with 57% ee
(Scheme 3).
Also most promising were first reactions with aliphatic
and unconjugated ketones. Thus, ketones 22–28 were reduced
under the same conditions as described above to alcohols 29–
35 in acceptable yields and with moderate to high enantio-
selectivity (Scheme 4).
Scheme 4. Enantioselective reduction of aliphatic ketones under the
conditions used for the reactions in Table 2.
The reaction mechanism of our transformations seems to
resemble that suggested by Noyori and co-workers,[11] since in
contrast to 36 the cyclodextrinyl–prolinol–Ru complex 37 was
completely unreactive, thus indicating the significance of the
À
N H group for hydrogen transfer to the carbonyl group
(Scheme 5).
Scheme 3. Reduction of the a-ketoester 20.
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finished after 24 h at room temperature. The mix-
ture was then extracted three times with hexane
(5 mL), the combined hexane extracts were washed
with water (6 mL) and dried over Na2SO4, and the
product(s) were analyzed by GC/HPLC and/or
purified by TLC. The ee values of the products
were determined by HPLC on
a chiral phase
(chiracel OD-H), GC on a chiral phase (hydro-
dex 3P), and 1H NMR/19F NMR spectroscopic stud-
ies of the corresponding Mosher esters.
Scheme 5. Suggested hydrogen transfer (Re attack) from the Ru–hydride intermediate to geranyl
acetone (26) encapsuled in b-cyclodextrin (see 36); the reaction in 37 fails.
Received: March 23, 2004
Revised: August 23, 2004
In summary, we have synthesized new water-soluble Ru
Keywords: asymmetric catalysis · cyclodextrins · reduction ·
ruthenium · transfer hydrogenation
.
complexes of b-cyclodextrin-modified amino alcohols 2 and 3
to serve as supramolecular catalysts in hydrogen-transfer
reactions. Up to 97% ee and good to excellent yields were
observed. In all cases, b-cyclodextrin plays an important role
on the enantioselectivity through preorganization of the
substrates in the hydrophobic cavity. This finding is partic-
ularly significant in the case of substrates such as 22–28.
Although a number of highly enantioselective Ru-based
hydrogen-transfer catalysts are known,[14] including one
example that functions in water,[15] none of these systems
have been shown to reduce unconjugated ketones.
[1] a) K. Takahashi, Chem. Rev. 1998, 98, 2013; b) J. Szejtli, Cyclo-
dextrins and their Inclusion Complexes, Academiai Kiado,
Budapest, 1982.
[2] a) J.-M. Lehn, Supramolecular Chemistry, VCH, Weinheim,
1995; b) Comprehensive Supramolecular Chemistry (Eds.: J. L.
Atwood, J. E. D. Davies, D. D. MacNicol, F. Vögtle), Pergamon,
Oxford, 1996.
[3] R. Breslow, Acc. Chem. Res. 1980, 13, 170.
[4] R. R. French, P. Holzer, M. Leuenberger, W.-D. Woggon,
Angew. Chem. 2000, 112, 1321; Angew. Chem. Int. Ed. 2000,
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[6] K. K. Park, J. W. Park, W.-J. Sim, J. Inclusion Phenom. Mol.
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[7] A. Deratani, E. Renard, F. Djedaini-Pilard, B. Perly, J. Chem.
Soc. Perkin Trans. 2 1997, 1517.
[8] H. Sakuraba, N. Inomata, Y. Tanaka, J. Org. Chem. 1989, 54,
3482.
[9] R. R. French, J. Wirz, W.-D. Woggon, Helv. Chim. Acta 1998, 81,
1521.
[10] M. A. Bennett, A. K. Smith, J. Chem. Soc. Dalton Trans. 1974,
233.
[11] a) R. Noyori, M. Yamakawa, S. Hashiguchi, J. Org. Chem. 2001,
66, 7931; b) M. Yamakawa, H. Ito, R. Noyori, J. Am. Chem. Soc.
2000, 122, 1466; c) D. A. Alonso, P. Brandt, S. J. M. Nordin, P. G.
Andersson, J. Am. Chem. Soc. 1999, 121, 9580.
[12] a) J. Takehara, S. Hashiguchi, A. Fujii, S. Inoue, T. Ikariya, R.
Noyori, Chem. Commun. 1996, 233; b) R. Noyori, Adv. Synth.
Catal. 2003, 1–2, 345.
[13] D. G. I. Petra, J. N. H. Reek, J.-W. Handgraaf, E. J. Meijer, P.
Dierkes, P. C. J. Kamer, J. Brussee, H. E. Schoemaker,
P. W. N. M. van Leeuwen, Chem. Eur. J. 2000, 6, 2818.
[14] R. Noyori, Angew. Chem. 2002, 114, 2108; Angew. Chem. Int. Ed.
2002, 41, 2008.
[15] a) H. Y. Rhyoo, H.-J. Park, Y. K. Chung, Chem. Commun. 2001,
2064; b) H. Y. Rhyoo, H.-J. Park, W. H. Suh, Y. K. Chung,
Tetrahedron Lett. 2002, 43, 269.
[16] The concentrations of the catalyst (10 mol%) and formate
(excess) were adjusted to give a reasonable reaction time of
approximately 24 h. Decreasing the catalyst and/or formate
concentration led to unsuitably long reaction times. Preliminary
Experimental Section
Synthesis of 2: Aneat solution of mono( O-6-tosyl)-b-cyclodextrin
(265 mg, 0.20 mmol) and aminoethanol (960 mg, 15.7 mmol,
80 equiv) was stirred for 12 h at 708C. Water was then added
(1.0 mL), and the resulting yellow solution was added dropwise to
acetone (60 mL). The resulting white precipitate (245 mg) was
filtered off and recrystallized from water to give pure 2 (140 mg,
59%). MS(ESI): m/z 1179 (M+, 100), 612 ([M+Na]2+, 72), 1201
([M+Na]+, 67); 1H NMR (600 MHz, D2O): d = 4.97–5.02 (m, 7H),
3.79–3.86 (m, 8H), 3.68–3.77 (m, 19H), 3.44–3.50 (m, 13H), 3.33 (dd,
J = 9.60, 9.60 Hz, 1H), 2.92 (d, J = 10.86 Hz, 1H), 2.69 (m, 1H),
2.54 ppm (m, 2H); m.p.: decomposition > 2758C.
Synthesis of 3: Aneat solution of mono( O-6-tosyl)-b-cyclo-
dextrin (300 mg, 0.23 mmol) and (S)-(+)-2-aminopropanol (1.4 g,
18.6 mmol, 80 equiv) was stirred for 12 h at 708C. Water (0.5 mL) was
then added, and the resulting yellow solution was added dropwise to
acetone (60 mL). The white precipitate (300 mg) was removed by
filtration and recrystallized from water. The white crystals were
washed with an ice-cold acetone/water mixture (1:1, 5 mL) to give
pure
3
(181 mg, 66%). MS(ESI): m/z 1192 (M+, 100), 618.5
([M+Na]2+, 85) 1214 ([M+Na]+, 78); 1H NMR (600 MHz, D2O):
d = 5.00–5.05 (m, 7H), 3.87–3.94 (m, 8H), 3.76–3.85 (m, 19H), 3.48–
3.63 (m, 13H), 3.38 (dd, J = 9.60, 9.60 Hz, 1H), 3.02 (d, J = 10.86 Hz,
1H), 2.79–2.82 (m, 1H), 2.54–2.57 (m, 2H), 1.09 (d, J = 6.32 Hz, 3H);
m.p.: decomposition > 2758C. Crystal data for 3: C45H77NO35·16H2O,
orthorhombic, P21, a = 12.8092(4) Š, b = 19.6407(5) Š, c =
26.2645(5) Š, a = 908, b = 908, c = 908, V= 6696.3 Š3, Z = 4, 1calcd
1.47, 85399 reflections were measured, T= 173 K. Data were
collected with MoKa radiation on a Bruker diffractometer (KAP-
PACCD and scantype PHIOMEGA).
=
6 (formed in situ): MS (ESI): m/z = 1191 ([ligand 3]+, 100), 1371
([6-Cl]+, 11), 1406 ([6]+, 18); UV/Vis (H2O): lmax = 251 nm.
General procedure:[16] Ligand 3 (0.01 mmol) was dissolved in
H2O/DMF (3:1, 0.5 mL), [RuCl2(C6H6)]2 (4, 0.005 mmol) was added,
and the resulting mixture was stirred for 1 h at room temperature.
HCOONa (1.0 mmol) was then added, and after further stirring for
10 min the ketone (0.1 mmol) was injected. The reaction was usually
À
À
experiments in which Ru O was replaced by Ru NTos revealed
a sixfold increase in the rate of the reaction, thus allowing for
lower catalyst loadings; results will be reported in a subsequent
publication.
6734
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Angew. Chem. Int. Ed. 2004, 43, 6731 –6734