High performance of Rh(Phebox) catalysts in asymmetric reductive aldol reaction: High anti-selectivity

Article abstract of DOI:10.1021/ja050698m

Chiral rhodium(bisoxazolinylphenyl) complexes (1 mol %) efficiently catalyze the asymmetric reductive aldol reaction of aldehydes and α,β-unsaturated esters at 50 °C for ca. 0.5-1.0 h with several hydrosilanes to give the corresponding β-hydroxypropionates with extremely high anti-selectivity (up to 98%) and enantioselectivity (up to 96% ee). The stereochemical outcome is likely due to a chairlike cyclic transition state involving rhodium-(E)-enolate. Copyright

Full text of DOI:10.1021/ja050698m

Published on Web 04/26/2005
High Performance of Rh(Phebox) Catalysts in Asymmetric Reductive Aldol
Reaction: High Anti-Selectivity
Hisao Nishiyama,* Takushi Shiomi, Yasunori Tsuchiya, and Isamu Matsuda
Department of Applied Chemistry, Graduate School of Engineering, Nagoya UniVersity, Chikusa,
Nagoya 464-8603, Japan
Received February 2, 2005; E-mail: hnishi@apchem.nagoya-u.ac.jp
Scheme 1
Reductive aldol reaction (RA) of R,â-unsaturated esters or enones
with aldehydes promoted by a catalytic amount of certain transition-
metal complexes and stoichiometric hydrosilanes is one of the most
promising aldol reaction alternatives, offering an advantage of in
situ generation of enolates as nucleophilic condensation counterparts
(eq 1).1-3 An impressive extension has been demonstrated by
Morken et al. with chiral phosphine-rhodium or nitrogen-based
ligand-iridium catalysts attaining asymmetric induction accom-
panied with syn-diastereoselectivity.4 RA is, nevertheless, still a
developing reaction paradigm of C-C bond formation in terms of
efficiency, control of stereochemistry, and asymmetric induction,
for example, loading amounts of unsaturated carbonyls and silanes
toward substrate aldehydes, or lower to moderate yields depending
on substrates. We disclose here a reasonable protocol producing
aldol compounds, â-hydroxyesters, with our chiral rhodium cata-
lysts.
Table 1. Asymmetric Reductive Aldol Reaction of tert-Butyl
Acrylate and Benzaldehyde with Rh(Phebox) Catalystsa
%ee
temp/time
C/h)
yield of 3
run
catalyst
silane
(
°
(%)
anti:syn
anti
syn
1
2
1
1
1
1
1
1
1
2
2
2
S1
S2
S2
S3
S4
S5
S6
S1
S2
S5
50/0.5
50/0.5
50/0.5
50/0.5
60/3.0
50/0.5
50/5.0
50/0.5
50/1.0
50/0.5
93
91
91
87
89
93
95
92
98
93
94:6
95:5
95:5
94:6
93:7
94:6
93:7
95:5
98:2
94:6
94
91
92
88
93
95
96
95
94
96
2
11
4
4
7
3b
4
5
6
7
8
9
10
5
34
65
57
54
We have so far reported chiral 2,6-bis(2-oxazolinyl)phenyl
skeleton (abbreviated as Phebox) as a C2-symmetric N-C-N ligand
and its transition metal complexes, which exhibit high potentiality
as Lewis acids in asymmetric reactions.5 Very recently, we have
found that Rh(Phebox) complexes act as efficient catalysts for the
asymmetric conjugate reduction of R,â-unsaturated esters with
several hydrosilanes.6 On the basis of this finding, we have reasoned
that a chiral Rh-Phebox catalyst could promote the asymmetric
RA reaction.
a Benzaldehyde (1.0 mmol), catalyst (0.01 mmol), tert-butyl acrylate (1.5
mmol), silane (1.6 mmol), toluene (3 mL). S1, (EtO)Me2SiH; S2,
(EtO)2MeSiH; S3, (EtO)3SiH; S4, Et2MeSiH; S5, Me2PhSiH; S6, MePh2SiH.
b Catalyst (0.001 mmol, 0.1 mol %).
Alkylhydrosilanes S4, S5, and S6 similarly worked to give 93-
96% ee (runs 5-7). Compared to the isopropyl complex 1, the
benzyl 2 was slightly effective to give 98% of anti-selectivity (runs
8-10). Other reaction profiles are as follows: enantiomeric excess
of the syn-product proved to be lower in all cases in 2-65%. At
20 °C, the aldol reaction did not take place. The catalysts could be
recovered as the chloride complex, Rh(Phebox-R)Cl2(H2O), by
elution with ethyl acetate from silica gel residue after chromato-
graphic separation of the aldol products.7
Aromatic aldehydes 4-9 were subjected to the reaction to also
give high anti-selectivity up to 98% and high enantioselectivity up
to 96% ee (Table 2). Although the cinnamaldehydes 10 and 11
and the aliphatic aldehydes 12 and 13 resulted in lower yields under
the same condition, their stereoselectivity could be improved by
changing the loading of acrylate or by choice of the hydrosilanes.
The reaction of tert-butyl crotonate 14 efficiently gave anti-15
in 97% ee (93% yield, anti:syn ) 93:7) with the catalyst 1 and the
silane S5 under the same condition for run 1 of Table 1. Methyl
methacrylate 16 resulted in 61 and 55% ee for 17.
The reaction was carried out at 50 °C as a standard condition by
dropwise addition of hydrosilane into a mixture of benzaldehyde
(1.0 mmol), tert-butyl acrylate (1.5 mmol), and the catalyst 1 (1
mol %) in toluene. The reaction was completed within 0.5-1.0 h
to form the corresponding aldol-silyl ethers, which were treated
under an acid condition (aq HCl) to give the mixture of 3anti and
3syn (Scheme 1). Alkoxyhydrosilanes S1, S2, and S3 smoothly
promoted the reduction-condensation process to give high yields
of 87-93% (Table 1). The anti-isomer, 3anti, was selectively
obtained in the ratio of 94:6-95:5 with high enantioselectivity up
to 94% (runs 1-4). Under the same condition, the catalyst loading
could be reduced to 0.1 mol % to keep the efficiency (run 3).
To clarify the mechanism, several experiments were carried out
as follows: in the absence of an acceptor benzaldehyde, the
conjugate reduction of methyl acrylate with Me2PhSiH S5 and the
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J. AM. CHEM. SOC. 2005, 127, 6972-6973
10.1021/ja050698m CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Asymmetric Reductive Aldol Reaction of Several
Aldehydes and tert-Butyl Acrylate with Rh(Phebox) Catalystsa
Figure 1. Hypothetical stereochemical course of the reaction.
one vacant site of the enolate complex. A final step is the release
of aldol products in the reductive elimination process, regenerating
the RhI(Phebox) species. Judging from the stereochemical outcome
of anti-(2R,3S), a chairlike transition state of Zimmerman-Traxler-
type can be hypothesized involving the Rh-(E)-enolate species,
which attacks the si face of the coordinating benzaldehyde (Figure
1).12 Experimental study of the mechanistic detail is now underway.
In conclusion, we have thus found a new efficient catalytic
system for the highly anti-selective and enantioselective reductive
aldol reaction of acrylates and aldehydes with hydrosilanes.
Supporting Information Available: Experimental details and
analysis. This material is available free of charge via the Internet at
http://pubs.acs.org.
References
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a Aldehyde (1.0 mmol), catalyst (0.01 mmol), tert-butyl acrylate (1.5
mmol), silane (1.6 mmol), toluene (3 mL), 50 °C, 0.5-1.0 h. b tert-Butyl
acrylate (2.0 mmol), silane (2.1 mmol).
catalyst 1 smoothly proceeded at 50 °C for 1 h to form a mixture
of the corresponding Z:E silylketene acetal, which was analyzed
by 1H NMR; Z:E ) 5:95.8 To the reaction mixture was then added
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benzaldehyde. However, the aldol reaction did not proceed at 50
°C for 5 h. This fact intensively suggests that the aldol reaction
takes place on the rhodium metal. The intermediary species may
be Rh-O-enolate as demonstrated by Bergman-Heathcock9 or
Rh-oxa-π-allyl as proven by Hayashi.10 While, with (EtO)2MeSiH
(S2) the reaction of the generated silylketene acetal and benzalde-
hyde proceeded at 50 °C for 5 h to give the aldol products in 68%
with high syn-selectivity (3anti:3syn ) 5:95); the intermediate
silylketene acetal (Z:E ) 39:61) was detected by NMR.8 The major
syn-product proved to be racemic. Thus, the background aldol
reaction was observed in the case of the alkoxysilane, probably
because of Lewis acidity of the incorporated alkoxysilyl moiety.11
However, it does not influence enantioselectivity of the anti-aldol,
very fortunately. It is thought that the starting RhIII(Phebox) complex
can be reduced with hydrosilane via RhI(Phebox) species to form
the H-RhIII(Phebox) species, which reacts with R,â-unsaturated
ester to give RhIII-enolate. Benzaldehyde is, in turn, captured on
(6) Tsuchiya, Y.; Kanazawa, Y.; Shiomi, T.; Kobayashi, K.; Nishiyama, H.
Synlett 2004, 2493-2496. Tsuchiya, Y.; Uchimura, H.; Kobayashi, K.;
Nishiyama, H. Synlett 2004, 2099-2102.
(7) Rh(Phebox-ip)Cl2(H2O) catalyzed the reaction with S2 at 50 °C to give
54% yield (anti:syn ) 84:16, 85% ee for anti and 4% ee for syn).
(8) See the experimental data with methyl acrylate in the Supporting
Information.
(9) Slough, G. A.; Bergman, R. G.; Heathcock, C. H. J. Am. Chem. Soc.
1989, 111, 938-949.
(10) Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, J. Am. Chem. Soc.
2002, 124, 5052-5058.
(11) Similar two-step RA with syn-selectivity was reported: Zhao, C.-X.; Bass,
J.; Morken, J. P. Org. Lett. 2001, 3, 2839-2842.
(12) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79, 1920-
1923. The transition state was presumed by calculation of the hypothetical
intermediates, rhodium-aldolate diastereomers; see, Supporting Information.
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