Highly effective chiral ortho-substituted BINAPO ligands (o-BINAPO): Applications in Ru-catalyzed asymmetric hydrogenations of β-aryl-substituted β-(acylamino)acrylates and β-keto esters

Article abstract of DOI:10.1021/ja020121u

A novel family of chiral ortho-substituted BINAPO ligands (o-BINAPO) were synthesized from BINOL, and their Ru complexes were highly efficient catalysts for asymmetric hydrogenation of β-aryl-substituted β-(acylamino)acrylates and β-aryl-substituted β-keto esters. The Ru-bisphosphinite catalysts can tolerate an E/Z mixture of β-aryl-substituted β-(acylamino)acrylates. These highly enantioselective hydrogenations provide a useful way to prepare β-aryl-substituted β-amino acids and β-hydroxyl acids. Copyright

Full text of DOI:10.1021/ja020121u

Published on Web 04/12/2002
Highly Effective Chiral Ortho-Substituted BINAPO Ligands (o-BINAPO):
Applications in Ru-Catalyzed Asymmetric Hydrogenations of
â-Aryl-Substituted â-(Acylamino)acrylates and â-Keto Esters
Yong-Gui Zhou, Wenjun Tang, Wen-Bo Wang, Wenge Li, and Xumu Zhang*
Department of Chemistry, The PennsylVania State UniVersity, 152 DaVey Laboratory,
UniVersity Park, PennsylVania 16802
Received January 23, 2002
Scheme 1
During the last several decades, many effective chiral bisphos-
phines have been developed. However, there is no solution in
dealing with many transition metal-catalyzed asymmetric transfor-
mations since enantioseletivities are often substrate-dependent.
Subtle changes in conformational, steric, and electronic properties
of chiral ligands can lead to dramatic variations of reactivities and
enantioselectivities. Conformationally rigid and tunable chiral
ligands offer a great advantage for optimizing the enantioselectivty
of a reaction. Herein, we like to report ruthenium catalysts with a
novel family of BINOL-derived phosphinite ligands for the first
highly enantioselective hydrogenation of â-aryl-substituted â-(acyl-
Table 1. Asymmetric Hydrogenation of â-Aryl-Substituted
amino)acrylates. These catalysts are also effective for highly
â-(Acylamino)acrylates 3a
enantioselective hydrogenation of â-aryl-substituted â-keto esters.
Noyori and co-workers have demonstrated that highly skewed
BINAP was an effective ligand for many asymmetric catalytic
reactions.1,2 A comparison of the structure of BINAP with the less-
effective BINAPO ligands3 reveals two possible reasons: (1) the
entry
ligands
Ar of 3
Rof 3
ee (%)b
config.c
oxygen atoms in the BINAPO increase the distance between the
chiral binaphthyl moiety and PPh2 groups and therefore decrease
the influence of chiral binaphthyl on orientation of the phenyl groups
of PPh2 and (2) the presence of the C-O-P bond in BINAPO
increases the flexibility of backbone. To develop highly effective
BINAPO ligands, we have designed ligands 2a-d by introducing
groups into 3,3′-positions of the binaphthyl backbone (ortho-
substitued BINAPO, abbreviated as o-BINAPO): introduction of
3,3′-R groups can restrict the orientation of Ar groups adjacent to
phosphine atoms. In addition, tuning of the steric and electronic
properties can be achieved by changing the R and Ar groups of
ligands. These ligands can be synthesized from the corresponding
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
BINAPO
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me (3a)
Me (3a)
Me (3a)
Me (3a)
Me (3a)
Me (3a)
Me (3a)
Me (3b)
Me (3c)
Me (3d)
Me (3e)
Me (3f)
Me (3g)
Me (3h)
Et (3i)
2 (5a)
22 (5a)
98 (5a)
99 (5a)
97 (5a)
31 (5a)
39 (5a)
99 (5b)
97 (5c)
97 (5d)
99 (5e)
99 (5f)
96 (5g)
80 (5h)
98 (5i)
98 (5j)
95 (5k)
93 (5l)
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
2a
2b
2c
2d
BINAP
MeO-Biphep
2c
2c
2c
2c
2c
2c
2c
2c
2c
2c
2c
p-F-C6H4
p-Cl-C6H4
p-Br-C6H4
p-Me-C6H4
p-MeO-C6H4
o-Me-C6H4
o-MeO-C6H4
Ph
4
diols (Scheme 1).
Enantiomerically pure â-amino acids and their derivatives are
important building blocks for the synthesis of â-peptides, â-lactam
antibiotics, and many important drugs.5 Recently, several synthetic
methodologies have been developed to make â-amino acids by using
stoichiometric chiral auxiliaries and catalytic methods,6 Among
these methods, straightforward asymmetric hydrogenation of â-ami-
noacrylic acid derivatives represents one of the simplest routes.
Previous attempts at asymmetric hydrogenation of â-(acylamino)-
acrylates using Ru7 and Rh8 catalysts led to moderate to good
enantioselectivity. The main issue is that the different catalytic
behaviors (ee values, catalytic activities) exist with Z- and E-
isomeric substrates. For example, (E)-methyl 3-acetamido-2-
butenoate gave 96% ee in Noyori’s Ru-BINAP system,7 while (Z)-
methyl 3-acetamido-2-butenoate gave only 5% ee with the opposite
configuration. So far, only moderate ee can be obtained with Rh-
p-F-C6H4
p-Cl-C6H4
p-Br-C6H4
Et (3j)
Et (3k)
Et (3l)
a The absolute configurations were determined by comparing optical
rotations with reported values. The reaction was carried out under 80 psi
of H2 in EtOH at 50 °C for 20 h, substrate/[Ru(p-cymene)Cl2]2/ligand )
50/1/2.1. b The ee (%) values were determined by GC using a chiralselect
1000 column. c Determined by the sign of rotations.
DuPhos8c and Ru-BINAP7 systems for hydrogenation of â-aryl-
substituted â-(acylamino)acrylates.
To test the synthetic utility of bisphosphinite ligands 2, we have
explored the Ru-catalyzed asymmetric hydrogenation of â-aryl-
substituted â-(acylamino)acrylates 3 (Table 1). Substrates 3a-l (E/Z
) 5/95 to 40/60) can be made from the â-keto esters 4 according
to a literature procedure.8c,9 The E/Z mixture of enamides 3a-l
cannot be separated by silica gel column chromatography. The Ru
catalyst was prepared by mixing the [Ru(p-cymene)Cl2]2 and a
* Corresponding author. E-mail: xumu@chem.psu.edu.
9
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J. AM. CHEM. SOC. 2002, 124, 4952-4953
10.1021/ja020121u CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Asymmetric Hydrogenation of â-Keto Esters 4a
have been achieved with most substrates (93-99% ee) except for
4f and 4g. Under the same reaction conditions, we examined the
enantioselectivties for hydrogenation of 4a: BINAP (80% ee),
MeO-BIPHEP (88%), BINAPO (29%), 2a (29%), 2b (94%), 2c
(99%), and 2d (97%). The enantioselectiVities achieVed with Ru-
2c as the catalyst are the highest reported for substrate 4a. For
hydrogenation of â-alkyl-substituted â-keto esters, we found that
o-BINAPO (2d) is a better ligand (entries 9-11).
In conclusion, we have developed a novel family of chiral
bisphosphinite ligands for enantioselective Ru-catalyzed hydrogena-
tion. These catalysts are especially effective for hydrogenation of
â-aryl-substituted â-(acylamino)acrylates and â-aryl-substituted
â-keto esters. The highly enantioselective hydrogenation provides
a useful way to prepare â-aryl-substituted â-amino acids and
â-hydroxyl acids. Further studies of other transition metal com-
plexes of these ligands and their applications are in progress.
entry
ligand
Ar of 4
Rof 4
ee (%) of 6b
config.c
1
2
3
4
5
6
7
8
9
2c
2c
2c
2c
2c
2c
2c
2c
2d
2d
2d
Ph
Et (4a)
Et (4b)
Et (4c)
Et (4d)
Et (4e)
Et (4f)
Et (4g)
Et (4h)
Me (4i)
Et (4j)
Et (4k)
99 (6a)
93 (6b)
98 (6c)
96 (6d)
95 (6e)
87 (7f)
90 (6g)
98 (6h)
96 (6i)
96 (6j)
98 (6k)
R
R
R
R
R
R
R
R
S
p-F-C6H4
p-Cl-C6H4
p-Br-C6H4
p-Me-C6H4
p-MeO-C6H4
o-Me-C6H4
o-MeO-C6H4
Me
10
11
Me
ClCH2
S
R
Acknowledgment. This work was supported by grants from
National Institute of health.
a The absolute configurations were determined by comparing optical
rotations with reported values. The reaction was carried out under 80 psi
of H2 in EtOH/DCM (3/1) at 50 °C for 20 h, substrate/[Ru(p-cymene)Cl2]2/
ligand ) 200/1/2.1. b The ee (%) values were determined by GC using a
chiralselect 1000 column or HPLC with Chiralpak AS column. c Determined
by the sign of rotations.
Supporting Information Available: Full experimental procedure,
GC, HPLC data, and [R]D values of ligands 2 and hydrogenation
products 5 and 6 (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
bisphosphinite ligand 2 in situ in hot DMF.10 The reaction was
carried out under 80 psi of H2 in EtOH at 50 °C for 20 h. Although
ligands BINAPO and 2a-d show similar reactivity, the enantiose-
lectivity varied dramatically. For example, substrate 3a was reduced
with 2% ee using a Ru-BINAPO complex as the catalyst (entry 1).
The enantioselectivity increased to 22% with Ru-Me-o-BINAPO
(2a) (entry 2), Surprisingly, ee values increased dramatically when
an aryl was introduced in the o-BINAPO ligand (entries 3-5). Up
to 99% ee has been achieved with the Ru-2c catalyst (entry 4).
This result is superior to ee values obtained with other phosphine
ligands (entry 6, 31% ee with BINAP; entry 7, 39% ee with MeO-
BIPHEP).
A variety of â-aryl-substituted â-(acylamino)acrylates were
employed as substrates for the Ru-catalyzed hydrogenation reaction
with 2c as the ligand (Table 1). High enantiomerical excesses have
been achieved with the exception of 3h (entry 14). There is no
major electonic effect on the substitution pattern of 3 (96-99%
ee). A possible explanation of the low ee (80%) with o-methoxy-
substituted enamide 3h is that competing coordination of the
o-methoxy group exists in the Ru system. In this catalytic system,
methyl â-aryl-substituted â-(acylamino)acrylates gave slightly better
enantioselectivities than the corresponding ethyl â-aryl-substituted
â-(acylamino)acrylates.
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It is noteworthy that our catalytic system Ru-bisphosphinite can
tolerate an E/Z mixture of substrates. The ability to reduce the E/Z
mixture of â-aryl-substituted â-(acylamino)acrylates 3 is crucial
to practical synthesis of various â-aryl-substituted â-amino acids.
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Ru-2c as the catalyst for hydrogenation of 3 are the highest reported
to date.
In a related area, Ru-BINAP1,2 and other Ru-phosphine systems11
were efficient for reduction of â-alkyl-substituted â-keto esters, but
only moderate to good enantioselectivities were obtained for
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To further expand the utility of the o-BINAPO ligands system,
we have examined Ru-catalyzed enantioselective hydrogenation of
â-aryl-substituted â-keto esters (Table 2). High enantioselectivities
JA020121U
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J. AM. CHEM. SOC. VOL. 124, NO. 18, 2002 4953