Ru-catalyzed asymmetric hydrogenation of racemic aldehydes via dynamic kinetic resolution: Efficient synthesis of optically active primary alcohols

Article abstract of DOI:10.1021/ja0680109

A highly efficient asymmetric hydrogenation of racemic α-arylaldehydes via dynamic kinetic resolution has been developed by using [RuCl₂(SDPs)(diamine)] complexes as catalysts, providing chiral primary alcohols in excellent enantioselectivities. Copyright

Full text of DOI:10.1021/ja0680109

Published on Web 01/31/2007
Ru-Catalyzed Asymmetric Hydrogenation of Racemic Aldehydes via Dynamic
Kinetic Resolution: Efficient Synthesis of Optically Active Primary Alcohols
Jian-Hua Xie, Zhang-Tao Zhou, Wei-Ling Kong, and Qi-Lin Zhou*
State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai UniVersity, Tianjin 300071, China
Received November 9, 2006; E-mail: qlzhou@nankai.edu.cn
Scheme 1
Catalytic asymmetric hydrogenation is one of the most elegant
and reliable methods for the preparation of optically active
compounds and has been widely used in industry.1 Among the
numerous chiral catalysts developed in past decades, the Noyori
[RuCl2(BINAP)(diamine)] catalyst has proved to be the most
efficient, catalyzing the hydrogenation of prochiral ketones with
excellent enantioselectivity with an extremely high turn-over
number.2 Using different [RuCl2(diphosphine)(diamine)] catalysts,
a variety of chiral secondary alcohols now can be easily synthesized
from the hydrogenation of prochiral ketones in high enantiomeric
excesses.3 Although the chiral primary alcohols are exceedingly
Scheme 2
significant compounds for both academic research and industrial
production,4 few catalytic methods for their synthesis by asymmetric
hydrogenation have appeared in the literature.5
In the catalytic asymmetric hydrogenation of prochiral ketones,
at least one new stereogenic center was generated (Scheme 1, eq
1).6 However, no new stereogenic center was generated in the
hydrogenation of R-branched aldehydes, which makes the enan-
tiocontrol of the reaction extremely difficult. Thus, the asymmetric
hydrogenation of R-branched aldehydes still remains a challenge
to chemists.7 If a catalyst can selectively hydrogenate one of two
enantiomers of the racemic aldehyde and the remaining enantiomer
can be rapidly racemized under the same reaction conditions, then
ultimately two enantiomers of aldehyde will be fully converted to
primary alcohol enantioselectively (Scheme 1, eq 2). This process
is termed the asymmetric hydrogenation of racemic aldehydes via
dynamic kinetic resolution (DKR).8
Table 1. Asymmetric Hydrogenation of Racemic 1a with
[RuCl2(SDPs)(diamine)] Catalysts 3a
In studying the synthesis of biologically active compounds such
as chiral pesticides and enzyme inhibitors, we became interested
in developing methods for the asymmetric synthesis of chiral
primary alcohols. The complexes [RuCl2(SDPs)(diamine)] recently
developed by us,3f,9 were found to be competent catalysts for the
asymmetric hydrogenation of racemic R-branched aldehydes via
DKR, which provided a practical access to chiral primary alcohols
in high enantiomeric excess (up to 96% ee) and in high yields
(Scheme 2).
Initially, we chose as catalyst [RuCl2((S)-Xyl-SDP)((R,R)-
DPEN)] ((S,RR)-3a), which has been demonstrated to be very
efficient for asymmetric hydrogenation of ketones3f,9 and, as the
standard substrate, the commercially available R-phenylpropional-
dehyde (1a). When racemic 1a was hydrogenated in iPrOH
containing (S,RR)-3a and KOtBu (S/C ) 1000, [1a] ) 0.2 M,
[KOtBu] ) 0.04 M) under 50 atm of H2 at room temperature for 8
h, (S)-2-phenylpropan-1-ol (2a) was obtained in 95% yield with
69% ee (Table 1, entry 1). Systematic investigation of Ru com-
plexes with different combinations of chiral spirobiindane diphos-
phines and chiral diamines, showed that the complex [RuCl2((S)-
DMM-SDP)((R,R)-DACH)] ((S,RR)-3j) was the best choice of
catalyst (Table 1, entry 10).
entry
catalyst
SDPs
diamine
ee (%)b
1
2
3
4
5
6
7
8
9
(S,RR)-3a
(S,SS)-3b
(S,RR)-3c
(S,RR)-3d
(S,RR)-3e
(S,RR)-3f
(R,S)-3g
(S,S)-3h
(S,RR)-3i
(S,RR)-3j
(S)-Xyl-SDP
(S)-Xyl-SDP
(S)-SDP
(S)-An-SDP
(S)-Tol-SDP
(S)-DMM-SDP
(R)-Xyl-SDP
(S)-Xyl-SDP
(S)-Xyl-SDP
(S)-DMM-SDP
(R,R)-DPEN
(S,S)-DPEN
(R,R)-DPEN
(R,R)-DPEN
(R,R)-DPEN
(R,R)-DPEN
(S)-DAIPEN
(S)-DAIPEN
(R,R)-DACH
(R,R)-DACH
69
12
45
47
43
70
6
58
77
78
10
a Reaction conditions: S/C )1000, [1a] ) 0.2 mmol/mL, [tBuOK] )
0.04 mmol/mL, iPrOH, room temperature (25 to 30 °C), 50 atm of H2, 8 h,
100% conversion. b Determined by chiral GC (Supelco â-DEX 225 column).
The absolute configuration was S.
2. It is evident that a bulky alkyl group at the R-position of the
aldehydes 1 is crucial for obtaining high enantioselectivity. The
highest enantioselectivity (96% ee) was achieved in the hydrogena-
tion of the aldehyde with a i-Pr group at the R-position (Table 2,
entry 3). The position and electronic property of substituents on
the aryl ring of the substrate has very little influence on the enan-
tiomeric excess of products. The catalyst loading can be lowered
to 0.02 mol % (S/C ) 5000). Of special note, the hydrogenation
Using catalyst (S,RR)-3j, a range of racemic R-arylaldehydes 1
have been hydrogenated, and the results are summarized in Table
9
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J. AM. CHEM. SOC. 2007, 129, 1868-1869
10.1021/ja0680109 CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Asymmetric Hydrogenation of Racemic R-Arylaldehydes
1 Catalyzed by (S,RR)-3ja
less than 5% deuterium observed at the â-position, thus confirming
that the hydrogenation of aldehyde with [RuCl2(SDPs)(diamine)]
catalysts occurs on the carbonyl group.13
In conclusion, this Ru-catalyzed asymmetric hydrogenation of
racemic R-arylaldehydes via dynamic kinetic resolution provided
a highly efficient and economical method for the synthesis of chiral
primary alcohols. The method shows great potential for wide
application in the synthesis of optically active pharmaceuticals and
natural products.
entry
substrate
R
Ar
ee (%)b
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
Me
C6H5
C6H5
C6H5
C6H5
C6H5
78
86
Et
i-Pr
96 (91)c,d
92
c-Pent
c-Hex
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
Acknowledgment. We thank the National Natural Science
Foundation of China, and the “111” project (B06005) of the
Ministry of Education of China for financial support.
92
95
93
89
93
93
94
90
2-MeC6H4
2-ClC6H4
3-MeC6H4
3-MeOC6H4
4-MeC6H4
4-MeOC6H4
4-ClC6H4
2-Naphthyl
4-MeC6H4
4-MeOC6H4
9
Supporting Information Available: Experimental procedures, the
characterizations of substrates and products, and the analysis of ee
values of hydrogenation products (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
10
11
12
13
14
15
i-Pr
c-Hex
c-Hex
89
92
94
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a Reaction conditions are same as those in Table 1; 100% conversion.
b The ee values were determined by chiral GC or HPLC. The absolute
configuration was S. c The data in parentheses was obtained by using 0.02
mol % catalyst, 32 h. d An amount of 94% ee was obtained by using the
catalyst [RuCl2((R)-Xyl-BINAP)((R,R)-DACH)].
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Scheme 3
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of aldehyde 1k afforded the alcohol 2k in 94% ee (Table 2, entry
11). This product is the key intermediate for the synthesis of natural
product (1S,4S)-cis-7-methoxy-calamenene.10
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as a ketone. For asymmetric hydrogenation of 1-deuteriobenzaldehyde,
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The prepared chiral primary alcohols are very useful in the
synthesis of chiral pharmaceuticals, pesticides, and natural products.
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to (S)-2-(4-chlorophenyl)-3-methylbutanoic acid ((S)-4), which is
the key chiral intermediate for the preparation of pyrethroid pesticide
(S,S)-fenvalerate, in 97% yield without loss of optical purity
(Scheme 3). Quinolylmethoxyphenyl acetic acid derivatives were
important leukotriene receptor antagonists and lipoxygenase inhibi-
tors such as BAY × 100511 and can be easily synthesized by our
method. The hydrogenation of racemic substrate 5 with catalyst
(R,SS)-3j produced the chiral primary alcohol 6 in 97% yield with
90% ee (98% ee after recrystallization). Oxidation of the alcohol 6
by NaClO2/TEMPO gave the compound BAY × 1005 in 89% yield
with 98% ee (Scheme 3).12 These examples illustrate the wide
applicability of the catalytic asymmetric hydrogenation of alde-
hydes.
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(13) The catalyst [RuH(BH4)((S,RR)-3j)] and Noyori catalyst [RuH(BH4)((R)-
BINAP)((R,R)-DPEN)] were prepared and used to catalyze the hydrogena-
tion of 1c under base-free conditions. Both catalysts gave <5% ee of
enantioselectivity at 40% conversion. Ohkuma, T.; Koizumi, M.; Mun˜iz,
K.; Hilt, G.; Kabuto, C.; Noyori, R. J. Am. Chem. Soc. 2002, 124, 6508.
To determine that the asymmetric hydrogenation via DKR is
performed by hydrogenation of the carbonyl group, instead of the
enol form of aldehydes, a deuteration of 1c was carried out. The
1H NMR analysis of the hydrogenation product showed that the
majority of the deuteration took place at the R-position (58%), with
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