Axial chirality control by 2,4-pentanediol for the alternative synthesis of c3-tunephos chiral diphosphine ligands and their applications in highly enantioselective ruthenium-catalyzed hydrogenation of β-keto esters

Article abstract of DOI:10.1002/adsc.200900589

A highly efficient strategy for the synthesis of a series of C ₃*-TunePhos chiral diphosphine ligands was well established with several remarkable features. The synthetic utility of these ligands was explored for the ruthenium-catalyzed asymmetric hydrogenation of β-keto esters. Up to 99% ee values were achieved for the enantioselective synthesis of β-hydroxy acid derivatives, which are very important chiral building blocks for the synthesis of a variety of natural products and biologically active molecules.

Full text of DOI:10.1002/adsc.200900589

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DOI: 10.1002/adsc.200900589
Axial Chirality Control by 2,4-Pentanediol for the Alternative
Synthesis of C *-TunePhos Chiral Diphosphine Ligands and Their
3
Applications in Highly Enantioselective Ruthenium-Catalyzed
Hydrogenation of b-Keto Esters
a
a
a
b
a,
Xianfeng Sun, Wei Li, Guohua Hou, Le Zhou, and Xumu Zhang *
a
Department of Pharmaceutical Chemistry, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road,
Piscataway, NJ, 08854, USA
Fax : (+1)-732-445-6312; e-mail: xumu@rci.rutgers.edu
College of Science, Northwest A&F University, Yangling, Shaanxi 712100, Peopleꢀs Republic of China
b
Received: August 28, 2009; Published online: October 28, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900589.
Abstract: A highly efficient strategy for the synthe-
and established, including desymmetrization of pro-
[
8]
sis of a series of C *-TunePhos chiral diphosphine
chiral biaryls, kinetic resolution of racemic sub-
3
[
9]
ligands was well established with several remark-
able features. The synthetic utility of these ligands
was explored for the ruthenium-catalyzed asymmet-
ric hydrogenation of b-keto esters. Up to 99% ee
values were achieved for the enantioselective syn-
thesis of b-hydroxy acid derivatives, which are very
important chiral building blocks for the synthesis of
a variety of natural products and biologically active
molecules.
strates, and chirality transfer from central, axial and
[10]
planar symmetry. Significant progress was made by
Lipshutz et al., who introduced the use of enantio-
merically pure 1,2-diphenyl-1,2-ethanediol, 2,3-
butane ACHUTNGRENNUGd iol, 1,2-amino alcohols and 1,4-di-O-benzyl-
threitol as chiral auxiliaries for copper-medidated in-
tramolecular biaryl couplings via higher-order cup-
[
11]
rates. Sugimuraꢀs group also demonstrated a highly
efficient and widely applicable stereocontroller to
produce enantiomerically pure materials by utilization
of optically active 2,4-pentanediol as a chiral linking
Keywords: asymmetric catalysis; enantioselectivity;
hydrogenation; ruthenium
[12]
bridge between a reagent and a prochiral substrate.
The stereochemistries of the products can be strictly
controlled by only two small methyl groups or even
by a single methyl group in some cases. For instance,
optically pure BINOL, trinaphthol derivatives or even
As remarkable auxiliaries and scaffolds, chiral biaryls some unsymmetrical biaryl alcohols can be obtained
are widely applied in a large number of efficient ster- after biaryl coupling reactions followed by removal of
[
1]
[10g,13]
eodifferentiating reactions. Particularly, the atropi- the chiral tether.
someric C -symmetric binaphthyl or biphenyl bridged Pertinent to this concept, Chanꢀs and our groups re-
diphosphine ligands BINAP, H -BINAP, MeO- cently have introduced central-to axial chirality trans-
2
[
2]
[3]
8
[
4]
[5]
[6]
BIPHEP, SEGPHOS, P-Phos, and their ana- fer in the bisphosphine ligand synthesis with an ex-
logues (Figure 1) are well known as highly efficient
chiral ligands for a variety of transition metal-cata-
lyzed asymmetric transformations.
Traditionally, the most convenient access to these
chiral bidentate diphosphine ligands proved to be the
resolution of the racemic diphosphine oxides with
some chiral tartaric acids followed by fractional re-
[7]
crystallization. This resolution step is very tedious
and some times difficult for the further optimization
to obtain >99.5% a single enantiomer. To tackle Figure 1. Some chiral atropisomeric C -symmetric biaryl li-
2
these problems, various strategies have been reported gands.
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Xianfeng Sun et al.
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Scheme 1. An alternative synthetic route to the family of the C *-TunePhos.
3
tremely high diastereomeric aryl-aryl coupling reac-
[
14]
tion (>99.5%) and several other features. The pres-
ence of additional chiral centers on the ligand back-
bones was found to exert significant influence on the
enantioselectivity and activity of the catalysts in asym-
metric hydrogenations utilizing their highly modular
nature. As part of our continuing effort in designing
ligand scaffolds for asymmetric catalysts by using this
concept, Scheme 1 depicts the diastereoselective Ull-
mann coupling reaction for a highly efficient alterna-
tive synthetic route to the family of air-stable modular
C -Tunephos-type chiral diphosphine ligands (C *-
3
3
TunePhos 1).
Starting from 2-amino-3-nitrophenol 2, selective ac-
tivation of the amino group was achieved via a one-
pot diazotization-iodination sequence to give 2-iodo-
[
15]
nitrophenol 3 in 83% yield. The chiral bis(nitrophe-
nol ether) 5 was prepared by the Mitsunobu reaction
with (2S,4S)-pentanediol and 2-iodonitrophenol. The
double Mitsunobu reaction proceeded smoothly and
afforded a 78% yield of 5 in one hour under sonica-
tion conditions. The intramolecular Ullmann reaction
of iodide 5 carried out according to Kornblum and
Figure 2. X-ray crystal structure of intermediate 6 (ORTEP
drawing).
[17]
[
16]
Kendall in DMF solution, proceeded with surpris-
ing ease in very high yield (up to 98%) and >99%
1
diastereoselectivity based on H NMR analysis. A The optically active intermediate 7, obtainable by the
crystal of intermediate 6 suitable for X-ray diffraction reduction of the compound 6, can be converted into
was grown and analyzed, since it is an unknown com- the 2,2’-diiodo derivative 8 by diazotization and treat-
pound. The axial chirality S was assigned when com- ment with potassium iodide. The enantiomer diiodo 8
pared to the chiralities of carbon centers C-14 (R) was readily transformed to optically pure bisphos-
and C-16 (R) in the single crystal structure (Figure 2). phine ligands 1a and 1b in moderate yields by consec-
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Axial Chirality Control by 2,4-Pentanediol for the Alternative Synthesis of C *-TunePhos
3
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utive treatment with n-butyllithium and correspond-
We initiated our studies by screening catalysts 9a–e
ing diarylphosphine chlorides at low temperature.
on the asymmetric hydrogenation of standard sub-
Several features are highlighted in this new C *-Tu- strate ethyl benzoylacetate 10a, which potentially
3
nePhos synthetic strategy. First, the low hindered and leads to the useful pharmaceutical intermediate, ethyl
[
22]
strong electron-withdrawing bisnitro groups in com- (S)-3-hydroxy-3-phenylpropionate (11a).
The reac-
pound 5 facilitated the Ullmann coupling reaction, tion was performed in ethanol at 808C under 50 atm
giving the desired intermediate 6 in a very high yield. hydrogen pressure for 12 h. In the presence of com-
This strategy circumvents the problem in our initial plex 9a, up to 97% ee and 100% conversion were ob-
[
14d]
effort to attach bis(diethyl phosphonate) groups in served (Table 1, entry 1).
A systematic investiga-
this step, which led to a relatively low oxidative tion of electronic and steric effects of substituents on
[
14c]
homo-coupling yield.
Second, the introduction of ligand 1 indicated that the introduction of somewhat
the synthetically flexible intermediate 8 allows for the bulky 3,5-dimethyl (1b) and 4-methyl (1c) groups
convenient divergent incorporation of various Ar sub- gave the best results with 98% enantiomeric excesses
stituents of the PAr moieties in the last step, avoiding (Table 1, entries 2 and 3). This enantiomeric excess of
2
the requisite individual formation of the phosphinic 11a was much higher than when C -TunePhos (72%
3
or phosphinous moieties and any phosphine oxide re- ee) was employed as a ligand under the similar condi-
[
1]
[14b]
duction as described in traditional strategies. Third, tions.
However, much more hindered 3,5-di-tert-
the chiral linking bridge of the 2,4-pentanediol tether butyl (1d) and 4-methoxy-3,5-di-tert-butyl (1e) groups
is very simple and just flexible enough for the chirali- on the P-phenyl rings dramatically diminished the
ty transfer from central-to-axial in the Ullmann cou- enantioselectivities (Table 1, entries 4 and 5).
pling reaction with complete diastereodifferentiation
To assess the general efficiency of this catalytic
without unwanted intermolecular coupling; this system, the asymmetric hydrogenation reactions were
avoids tedious and time-consuming routine resolu- performed on a variety of 3-oxo-3-arylpropionic acid
tions. Finally, the ready availability of the enantiomer- ethyl esters using 9b as the catalyst (Table 2, en-
ically pure diiodide 8 of defined axial chirality has tries 1–9). Quantitative conversions with excellent
now opened up a possible direct access to asymmetric enantioselectivities (95–99% ee) were achieved. Hy-
diphosphines by applying the sequential monolithia- drogenation of 10 was not sensitive to the substituents
tion/monophosphination principle demonstrated pre- (o, p, electron-donating or electron-withdrawing) on
[
18]
viously by Murdoch and Achiwa.
the aromatic ring. The RuCl L* AHCTUNGTNERNUG( DMF) 9b catalyst
2 n
To systematically test the synthetic utility of this was also successfully applied to the asymmetric reduc-
TunePhos family of ligands in asymmetric hydrogena- tion of alkyl acetoacetates regardless of the bulkiness
tions, their analogous ligands 1c (Ar=4-Me-C H ), 1d of the alkyl group (Table 2, entries 10–12) giving up
6
4
[
Ar=3,5-(t-Bu) C H ] and 1e [Ar=4-MeO-3,5-(t- to 99% ees.
2 6 3
Bu) C H ] were also resynthesized by following our
In conclusion, a novel alternative route to a series
2
6
2
[
14c]
reported procedures.
The catalysts RuL*Cl2 of chiral C *-TunePhos bisphosphines has been de-
3
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(DMF)n 9a–e (where L* is the corresponding chiral
ligand 1a–e, n=2–6) were prepared as reddish brown
solids from [RuCl (benzene) ] and the corresponding
AHCTUNGTRENNUNG
2
2 2
Table 1. Ligand screenings for asymmetric hydrogenation of
[
19]
1
a–e in DMF at 1008C.
The complexes obtained ethyl benzoylacetate 10a.
were used directly in the catalytic reactions.
Optically active b-hydroxy acids and their deriva-
tives are very important structural motifs in numerous
biologically active compounds, especially medicines
[
7]
and functional materials. Accordingly, tremendous
effort has been devoted to their preparation via asym-
[1]
metric synthesis. Although the Ru-BINAP system
has been recognized as an efficient and general cata-
lyst for the hydrogenation of b-alkyl-substituted b-
keto esters, only inferior ee values were obtained for
[
20]
analogous b-aryl-substituted b-keto esters.
So far,
limited C -symmetrical bisphosphine ligands have
2
been reported to show good to excellent ee in the Ru-
catalyzed hydrogenation of b-aryl-substituted b-keto
[a]
The ee values were determined by GC on a chiral Beta
dex 390 capillary column.
b]
[21]
esters.
For example, up to 99% ee was achieved
[
21e,f]
’
[
with bisphosphinite ligands
and 4,4-substituted
The absolute configuration of 11a was assigned by com-
parison of the observed optical rotation with reported
data.
[21g]
BINAP ligands.
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Xianfeng Sun et al.
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Table 2. Ru-catalyzed asymmetric hydrogenation of b-keto
esters.
vials. To the catalyst solution was added the substrate
(0.25 mmol). The resulting mixture was transferred into an
autoclave and charged with H at 50 atm. The autoclave was
2
heated at 808C for 12 h. The autoclave was then cooled to
room temperature and the H was carefully released. The
2
reaction solution was then evaporated and the residue was
purified by column chromatography to give the correspond-
ing hydrogenation product, which was then directly analyzed
by GC (chiral Beta dex 390 or Gamma dex 225) or HPLC
(
Chiralpak AS) to determine the enantiomeric excess.
Acknowledgements
We would like to acknowledge the National Institutes of
Health (GM58832) and Merck & Co., Inc. for financial sup-
port. We would like to thank Dr. H. Yennane at The Pennsyl-
vania State University for the X-ray analyses. The assistance
of Dr. C. Pabba and Mr. R. Davis at Albany Molecular Re-
search Inc. in the preparation of the manuscript is also grate-
fully acknowledged.
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Enantiomeric excesses were determined by GC using
chiral Beta dex 390 and Gama dex 225 columns or
HPLC using a Chiralpak AS column.
The absolute configuration of 11 was assigned by com-
parison of the observed optical rotation with reported
data.
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