Matching and mismatching effects of hybrid chiral biaxial bisphosphine ligands in enantioselective hydrogenation of ketoesters

Article abstract of DOI:10.1002/chem.200900722

A study was conducted to demonstrate matching and mismatching of hybrid chiral biaxial bisphosphine ligands in enantioselective hydrogenation of ketoesters. A novel class of conformationally rigid C_n-TunePhos was developed by introducing a bridge with variable length to link the chiral atropisometic biaryl groups. The conformationally rigid C_n-TunePhos was introduce to investigate the synthesis and use of new chiral biophosphine ligands in asymmetric catalysis. A strategy was introduced for the synthesis of a pair of diastereoisomeric forms of ligands 1, 2, and an analogous ligand 3 to assess the effects of stereochemical matching and mismatching interactions upon the structural and catalytic properties of the corresponding ruthenium complexes. Their applications in highly efficient Ru-catalyzed asymmetric hydrogenation for the enantioselective synthesis of α- and β-hydroxy acid derivatives were also explored.

Full text of DOI:10.1002/chem.200900722

DOI: 10.1002/chem.200900722
Matching and Mismatching Effects of Hybrid Chiral Biaxial Bisphosphine
Ligands in Enantioselective Hydrogenation of Ketoesters
Xianfeng Sun,[a] Wei Li,[a] Le Zhou,[b] and Xumu Zhang*[a]
Catalytic asymmetric synthesis is a significant component
in modern organic chemistry. It has widely been used to pro-
duce a number of optically active compounds, from agro-
chemicals, to pharmaceuticals, to flavors, and fragrances as
well as functional materials.[1] One of the most important
methods to increase the stereoselectivity of reactions is mul-
tiple stereoselectivity (multiple stereodifferentiation, multi-
ple asymmetric induction), when the stereochemical process
proceeds under the control of more than one chiral auxili-
ary.[2] During the last two decades, these double stereoselec-
tive strategies have been successfully applied in a variety of
reactions, such as Sharpless dihydroxylation, Michael addi-
tions, addition to allyl metals, the Reformatsky reaction, the
Mukaiyama reaction, photochemical reactions, alkylation,
cycloadditions and the synthesis of heteroatom com-
pounds.[2] In contrast, catalytic systems with multiple stereo-
genic axial elements in chiral ligands are much less explored
in transition metal catalyzed asymmetric hydrogenations.
The multiple chiral elements in ligands may be situated fa-
vorably (“matched”) or unfavorably (“mismatched”) for ste-
reocontrol when the catalyst interacts with a prochiral sub-
strate. Ultimately, the matched cases may lead to dramati-
cally higher asymmetric induction in the products, whereas
the mismatched cases often result in significantly lower se-
lectivity in hydrogenation reactions.[3] Syntheses of these
molecules have facilitated a preliminary study of matching
and mismatching effects, relating backbone chirality and
phosphorus-based chirality with the performance of these li-
gands in asymmetric catalysis. The most notable achieve-
ments of catalytic systems with double asymmetric induction
exist in hydrogenation chemistry, focusing primarily on rho-
dium or ruthenium with bidentate phosphine ligands,[4] in
particular, modifications of DIOP,[5] BINAP,[6] dialkylphos-
pholane bis(phospholane) ligands,[7] and many others.[8] As
reported, configurational changes in ligands brought by in-
troducing additional chirality are generally unpredictable.
There are no reliable predictive models to explain the struc-
tural subtleties of catalysts with multiple chiral elements
that lead to dramatic changes in stereoselectivities.[9]
As part of our continued interest in the synthesis and use
of new chiral bisphosphine ligands in asymmetric catalysis,
we have developed a novel class of conformationally rigid
Cn-TunePhos (n=1–6) by introducing a bridge with variable
length to link the chiral atropisometic biaryl groups.[10] This
family of TunePhos ligands has proven to be highly efficient
in a variety of asymmetric reactions.[11] We envision that
changes of relatively flexible alkyl linker in the Cn-TunePhos
family with an aromatic group or a bulky chiral bridge may
enhance the rigidity and steric hindrance of the structure.
Consequently, unique steric or electronic effects and good
chiral discrimination could be expected. Herein we report a
convenient strategy for the synthesis of a pair of diastereo-
isomeric forms of ligands 1, 2 and an analogous ligand 3 in
order to assess the effects of stereochemical matching and
mismatching interactions upon the structural and catalytic
properties of the corresponding ruthenium complexes. Their
applications in highly efficient Ru-catalyzed asymmetric hy-
drogenations for the enantioselective synthesis of a- and b-
hydroxy acid derivatives were also explored.
[a] Dr. X. Sun, W. Li, Prof. X. Zhang
Department of Chemistry and
Chemical Biology & Pharmaceutical Chemistry
Rutgers, The State University of New Jersey
Piscataway, New Jersey 08854 (USA)
Fax : (+1)732-445-6312
E-mail: xumu@rci.rutgers.edu
This new series of bisphosphine ligands were prepare as
shown in Scheme 1: (R or S)-2,2’-dichloromethyl-1,1’-bi-
naphthyl (8) was synthesized in four steps with high yields
from readily accessible starting materials as developed in
our group.[12] (R or S)-2,2’-Bistriflate-1,1’-binaphthyl (5) was
obtained from (R or S)-binaphthol with excess trifluorome-
thane sulfonic anhydride and pyridine in CH2Cl2. Kumada-
[b] Prof. L. Zhou
College of Science
Northwest A&F University
Yangling, Shaanxi, 712100 (P. R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900722: Experimental proce-
dures and compound characterization data.
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COMMUNICATION
type coupling of bistriflate 5 with methylmagnesium bro-
mide gave (R or S)-2,2’-dimethyl-1,1’-binaphthyl (6) almost
in a quantitative yield. (R or S)-2,2’-Dibromomethyl-1,1’-bi-
naphthyl (7) was prepared by bromination of 6 with NBS. A
simple anion exchange of (R or S)-2,2’-dibromomethyl-1,1’-
binaphthyl (7) with LiCl afforded (R or S)-2,2’-dichloro-
methyl-1,1’-binaphthyl 8 in 93 % yield. HO-BIPHEP 10 can
be prepared after demethylation of enantiomerically pure
(S)-MeO-BIPHEP.[10] Reaction of 10 with the dichloride
compound 8 in the presence of excess anhydrous K2CO3 in
DMF formed new ligands (R,S)-1 or (S,S)-2 in moderate
yields. Using a similar procedure, we also made the corre-
sponding air-stable chiral monoaxial ligand 3 from the com-
mercially available staring material a,a’-dibromo-o-xylene
in one step. A key point in the last step of the synthesis was
to add 2,2’-dichloromethyl-1,1’-binaphthyl (8) dropwise with
a syringe pump in 36 h, which dramatically suppressed the
intermolecular byproducts. This efficient synthetic route
allows us to make the desired hybrid ligands in large scales.
With the availability of diastereomeric bisphosphine li-
gands 1, 2 and their analogous ligand 3, several interesting
questions were raised, as also mentioned in Burkꢁs report.[7]
For instance, “…could the two diastereomers afford compa-
rative results in catalysis? would significant matching and
mismatching effects be associated with the reactivity and se-
lectivity of catalysts bearing the diastereomeric ligands?
would the most reactive diastereomeric catalyst also corre-
spond to the most selective catalyst, or would these two
properties be independent?…”[7] To address these questions,
we have explored these ligands in asymmetric hydrogena-
tion of ketoesters.
Catalysts [RuL*Cl
sponding chiral ligand (R,S)-1, (S,S)-2 and (S)-3) were pre-
pared as reddish brown solid from [RuCl2A(benzene)2]2 and
2ACHTUNGTNER(NUNG dmf)n] 12a–c (where L* is the corre-
CTHUNGTRENNUNG
the hybrid ligands in DMF at 1008C for 30 min.[13] The com-
plexes obtained were used directly in the catalytic reactions.
To compare the catalytic efficiency and selectivity of the
two diastereomeric catalyst systems bearing ligands 1 and 2,
we first examined asymmetric hydrogenation of standard b-
ketoester substrate 13, which led to useful pharmaceutical
intermediate, (R)-3-hydroxyl-3-phenyl propionate 14
(Table 1). Under optimized conditions, the reaction was per-
formed in ethanol at 808C under 50 atm hydrogen pressure.
All three catalysts were found to be effective for this hydro-
genation, giving complete conversion over 12 h with
1 mol % catalyst loading. The enantioselectivities achieved
in these reactions were shown in Table 1. Relatively poor
enantioselectivity of 78 % ee was obtained with catalyst
from ligand 1. The catalyst containing ligand (S,S)-2 was
found to afford the product 14 with higher enantioselectivity
(Table 1, entry 2, 89 % ee) under the same reaction condi-
tions, suggesting that this ligand represents the desired
matched combination of stereochemical elements. Interest-
ingly, the analogous catalyst bearing the parent BIPHEP
backbone with only one chiral axial ligand (S)-3 performed
moderately in this reaction (Table 1, entry 3, 83 % ee). An-
other important finding was that in each case R enantiomer
of product was formed, regardless of the overall backbone
stereochemistry. Each of the ligands 1, 2, and 3 contains
BIPHEP moieties with S absolute configuration at the axis.
It may be deduced that the chirality of BIPHEP moiety con-
taining diphenyl phosphines influences the absolute stereo-
chemistry observed in hydrogenations when using ligands 1–
3. In other words, the chirality of BIPHEP backbone over-
rides the other bias imposed by the binaphthyl skeleton chir-
ality in these ligands. However, undoubtedly, the binaphthyl
linkers in the ligands not only restricted the free rotation of
the BIPHEP backbone affording a conformational rigid
structure, but also provided a unique chiral environment in
the catalytic hydrogenations.
Optically active a-hydroxy acids, b-hydoxy acids and their
derivatives represent an important class of building blocks
for the synthesis of natural products and biologically active
molecules, such as angiotensin converting enzyme inhibitors
(ACE): Benazepril, Delapril hydrochloride, and Clopidogre
bisulfate.[14]
Scheme 1. Synthesis of hybrid chrial biaxial diphosphine ligands.
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X. Zhang et al.
Table 1. Hydrogenations of b-ketoester with hybrid ligands.
mismatched complex 12a, the ee was improved to 85 % at
the cost of the low conversion (Table 2, entry 4). As can be
seen from entries 7–11 in Table 2, the solvent effect played
an important role in these reactions. Extremely low reactivi-
ty was observed in aprotic non-polar solvents such as
CH2Cl2, EtOAc, THF.
Entry
L*
Conv.
ee [%][a]
Configuration[b]
1
2
3
1
2
3
100
100
100
78
89
83
R
R
R
Under the optimized reaction conditions (Table 2,
entry 5), a variety of a-aryl substituted a-ketoesters 15a–j
were examined for hydrogenations with [RuL*Cl2ACHTUNGTRENNUNG(dmf)n]
[a] ee values were determined by GC on a Chiral select 1000 capillary
column. [b] The absolute configuration of 14 was assigned by comparison
of the observed optical rotation with reported data.
12b (Table 3). All selected a-ketoesters were reduced to
form chiral a-hydroxy esters with excellent enantioselectivi-
ties (94–97 %). The electronic and steric nature of a sub-
stituent on the phenyl ring of substrate had little influence
on the enantioselectivity and reactivity of the reaction. The
enantiomeric excess of 16 was comparable to or better than
those obtained when the analogous ligand C3-TunePhos was
used under exactly the same conditions (Table 3).[15] It was
noteworthy that, even without acidic additives,[1,3] ligand 2
showed remarkable selectivities compared to BINAP in the
hydrogenation of 15. A key intermediate for the synthesis of
ACE inhibitors Benazepril and Delapril hydrochloride[14]
was readily accessible via the hydrogenation of ethyl 2-oxo-
4-phenylbutyrate with up to 96 % ee (Table 3, entry 10). To
We next examined the asymmetric hydrogenation of
methyl benzoylformate (15a) using the ruthenium catalysts
bearing the ligands 1 and 2. The reactions proceeded
smoothly under rather harsh conditions (50 atm of hydrogen
pressure and 808C). As shown in Table 2, a similar trend ob-
served in the asymmetric reduction of substrate 13 was
found in the hydrogenation of 15a, when catalyst [RuL*Cl2-
ACHTUNGTRENNUNG(dmf)n] 12a and 12b were applied in the reaction. In the hy-
drogenation of a-ketoester 15a, the superior (matched)
ligand system for this reaction was found to be 12b, which
incorporated ligand (S,S)-2 (Table 2, entry 2, 88 % ee). On
the contrary, the catalyst Ru/1 resulted in a loss of stereo-
control (Table 2, entry 1, 64 % ee). Again, the BIPHEP
Table 3. Asymmetric hydrogenantion of a-aryl substituted a-ketoesters[a]
.
Table 2. Asymmetric hydrogenation of methyl benzoylformate.
ee [%][b]
R2 Product
ACTHNGUTERNNU(G S,S)-2 (S)-C3-TunePhos
Entry Substrate R1
1
2
3
4
5
6
7
8
9
15a
15b
15c
15d
15e
15 f
15g
15h
15i
Ph
Me 16a
Me 16b
Me 16c
Me 16d
Me 16e
95
97
95
94
93
92
96
96
95
85
96
Entry Catalyst Solvent
T
H2
Conv. ee
Configuration[b]
4-F-C6H4
3-F-C6H4
4-Cl-C6H4
4-Br-C6H4
4-Me-C6H4 Me 16 f
4-MeOC6H4 Me 16g
3-MeOC6H4 Me 16h
96
96
95
95
94
97
96
96
96
[8C] [atm] [%]
[%][a]
1
12a
12b
12c
12a
12b
12c
12b
12b
12b
12b
12b
MeOH 80
MeOH 80
MeOH 80
MeOH RT
MeOH RT
MeOH RT
CH2Cl2 RT
acetone RT
EtOAc RT
toluene RT
50
50
50
5
5
5
5
5
5
5
100
100
100
90
64
88
81
85
R
R
R
R
R
R
R
R
R
R
R
2
3
4
5
6
7
8
9
100
100
<5
<5
<5
<5
9
95
90
Me
Et
Me 16i
Et 16j
10
15j
N/A
N/A
N/A
N/A
58
[a] Conversions were >99% as indicated by 1H NMR for all entries.
[b] ee values were determined by chiral GC (see Experimental Section).
The absolute configurations of products were assigned as R by compari-
son of the observed optical rotation with reported data.
10
11
THF
RT
5
[a] ee values were determined by chiral GC (see the Experimental Sec-
tion). [b] The absolute configurations of products were assigned as R by
comparison of the observed optical rotation with reported data.
our best knowledge, these results represent one of the high-
est enantioselectivities yet achieved yet in the preparation
of optically active a-hydroxy acid derivatives using direct
asymmetric hydrogenations.
In conclusion, we have endeavored to design and synthe-
size the ligands containing double chiral axials in a bridging
unit in an effort to systematically control the conformation
of the backbone structure, while maintaining certain flexibil-
ity. In this manner, we not only can maintain high catalytic
activity associated with the large bite angle of the diphos-
phine moiety but also can optimize enantioselectivities
moiety stereochemistry dominated over the backbone chir-
ality, as all catalysts Ru/1, Ru/2 and Ru/3 afforded methyl
mandelate 16a with R absolute configuration.
Further optimization studies showed that the hydrogena-
tion can also proceed smoothly to completion with Ru/2 cat-
alyst within 20 h under very mild conditions (5 atm of hy-
drogen pressure and room temperature). This increased the
enantioselectivity up to 95 % (Table 2, entry 5). As for the
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Enantioselective Hydrogenation
COMMUNICATION
through the enforcement of a dominant backbone confor-
mation with an extra chiral auxiliary of the binaphthyl struc-
ture. Moreover, the presence of the chiral binaphthyl auxili-
ary within a backbone offers the opportunity to prepare dia-
stereomeric ligands that could display the effects of match-
ing and mismatching caused by interactions between the
two stereochemical axils within each ligand. Ruthenium cat-
alysts bearing each of the two diastereomeric ligand were
examined for effectiveness in hydrogenation reactions. The
selectivity data revealed that the matched ligand system was
(S,S)-2, which afforded much higher enantioselectivities in
hydrogenation of b-ketoesters and methyl benzoylformate,
in contrast to the analogous mismatched ligand (R,S)-1.
These highly enantioselective hydrogenation reactions pro-
vide facile access to optically active a- and b-hydroxy acid
derivatives, which are very important chiral building blocks
for the syntheses of a variety of natural products and biolog-
ically active molecules. Further exploration of the general
applications of this class of ligands in transition metal cata-
lyzed asymmetric reactions is under current investigation.
Keywords: asymmetric catalysis
hydrogenation · ruthenium
·
enantioselectivity
·
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Experimental Section
General hydrogenation procedure: [RuACHTNUGTRNEU(GN benzene)Cl2]2 (5 mg, 0.01 mmol)
and chiral ligand 1, 2 or 3 (0.021 mmol) were dissolved in degassed DMF
(3 mL) in a Schlenk tube and heated to 1008C under N2 for 30 min.
After the mixture was cooled to 508C, the solvent was removed under
vacuum to give the catalysts as a reddish brown solid. The catalyst was
taken into a glovebox, dissolved in degassed methanol (16 mL), and dis-
tributed equally among eight vials. To the catalyst solution was added the
substrate (0.25 mmol). The resulting mixture was transferred into an au-
toclave and charged with H2 (50 atm for substrate 13 and 5 atm for a-ke-
toesters 15). The autoclave was heated at 808C for 12 h for b-ketoester
or at room temperature for a-ketoester substrates for 20 h. The autoclave
was then cooled to room temperature and the H2 was carefully released.
The reaction solution was then evaporated and the residue was purified
by column chromatography to give the corresponding hydrogenation
product, which was then directly analyzed by chiral GC (Gamma dex 225
or Beta dex 390) to determine the enantiomeric excesses.
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Acknowledgement
[15] C.-J. Wang, X. Sun, X. Zhang, Synlett 2006, 1169.
This work was supported by the National Institutes of Health
(GM58832).
Received: March 20, 2009
Published online: June 25, 2009
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