Enantioselective hydrogenation of α-dehydroamino acid esters catalyzed by rhodium complexes with chiral bisaminophosphine ligands

Article abstract of DOI:10.1002/adsc.201000038

A highly efficient strategy for the synthesis of a series of chiral bisaminophosphine ligands was well established with several remarkable features. The synthetic utility of these ligands was explored for rhodium-catalyzed asymmetric hydrogenations of α-d

Full text of DOI:10.1002/adsc.201000038

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DOI: 10.1002/adsc.201000038
Enantioselective Hydrogenation of a-Dehydroamino Acid Esters
Catalyzed by Rhodium Complexes with Chiral
Bisaminophosphine Ligands
Xianfeng Sun,a Wei Li,a Le Zhou,b and Xumu Zhanga,*
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: January 15, 2010; Revised: March 12, 2010; Published online: April 22, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000038.
Abstract: A highly efficient strategy for the synthe-
sis of a series of chiral bisaminophosphine ligands
was well established with several remarkable fea-
tures. The synthetic utility of these ligands was ex-
plored for rhodium-catalyzed asymmetric hydroge-
nations of a-dehydroamino acid esters. Up to 98%
ee values were achieved for the enantioselective
synthesis of aminocarboxylic acids and their deriva-
tives, which are very important chiral building
blocks for the synthesis of a variety of natural prod-
ucts and biologically active molecules.
cently, Rh catalysts bearing aminophosphine ligands
have shown good to excellent enantioselectivities and
high reactivities in asymmetric hydrogenation.[8] For
example, H8-BDPAB and BDPAB, reported by Chan,
have been successfully applied for hydrogenation of
arylenamides.[8g,h] Xyl-BDPAB was also found to be
an efficient ligand for the asymmetric hydrogenation
of a-dehydroamino acid derivatives.[9] Jiangꢀs bisam-
AHCTUNGTREGUNiNN nophosphine ligand can be prepared in two steps
from C2-symmetrical (2R,3S,4S,5R)-2,5-diamino-1,6-
diphenyl-3,4-hexanediol, but only moderate results
were observed in the Rh-catalyzed asymmetric hydro-
genation.[10]
Recently, Chanꢀs and our groups have introduced
central-to-axial chirality transfer in the bisphosphine
ligand synthesis with an extremely high diastereo-
meric aryl-aryl coupling reaction (>99.5%) and sever-
al other remarkable features.[11] The presence of addi-
tional chiral centers on the ligand backbone was
Keywords: a-amino acids; asymmetric catalysis; a-
dehydroamino acids; enantioselectivity; hydrogena-
tion; rhodium
The increasing demands for enantiomerically pure found to exert a significant influence on the enantio-
pharmaceuticals, agrochemicals, and fine chemicals selectivity and activity of the catalysts in asymmetric
have promoted the development of asymmetric cata- hydrogenations. Herein, as part of our continuing ef-
lytic technologies dramatically.[1] During the last few forts in designing new ligand scaffolds for asymmetric
decades, significant attention has been devoted to the catalysts by using this concept, we have investigated
discovery of new catalysts for important asymmetric the synthesis and coordination chemistry of modular
reactions, such as allylamine isomerization, Michael and fine-tunable chiral bisaminophosphine ligands in
additions, nucleophilic substitution, alkene carbonyla- anticipation that the resulting phosphines would have
tion, etc.[2] Transition metals bound to diverse struc- different steric and electronic properties. Some asym-
tures of chiral phosphorus ligands have emerged and metric hydrogenation studies were explored as well.
become well established as preferential catalysts for
Scheme 1 depicts the diastereoselective Ullmann
asymmetric hydrogenation.[3] In contrast to the broad coupling reaction for the synthesis of these novel
success in the synthesis and applications of monoden- chiral bisaminophosphines 1. (6R,8R)-6,8-Dimethyl-
tate, C2-symmetrical or pseudo-C2-symmetrical biden- 1,13-dinitro-7,8-dihydro-6H-dibenzoACTHNUTRGENNUG[f,h]ACHTUNGTRENN[UGN 1,5]dioxonine
tate and multidentate phosphorus ligands in asymmet- 5 was synthesized in three steps with high yields from
ric reactions, only limited results obtained with phos- readily accessible starting materials as developed by
phinite,[4] phosphite,[5] phosphonite,[6] or phosphoro- our group.[12] Starting from 2-amino-3-nitrophenol 2,
ACHTUNGTRENNUNG
amidite[7] ligands have been reported so far. More re- selective activation of the amino group was achieved
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Enantioselective Hydrogenation of a-Dehydroamino Acid Esters
Scheme 1. Synthesis of modular and fine-tunable bisaminophosphine ligands.
via a one-pot diazotization-iodination sequence to ality transfer from central-to-axial in the Ullmann
give 2-iodonitrophenol 3 in 83% yield.[13] The chiral coupling reaction with complete diastereodifferentia-
bis(nitrophenol ether) 4 was prepared by a Mitsunobu tion without unwanted intermolecular coupling; this
reaction with (2S,4S)-pentanediol and 2-iodonitrophe- avoids tedious and time-consuming routine resolu-
nol. The double Mitsunobu reaction proceeded tions. Finally, the attractiveness of this ligand class is
smoothly and afforded 78% yield in one hour under found in the modular character of the diaminopho-
sonication conditions. The intramolecular Ullmann re- phine derivatives, which are easily accessible and
action of iodides 4, carried out according to Korn- stable compounds.
blum and Kendall[14] in DMF, proceeded with surpris-
ing ease in a very high yield (up to 98%) and >99% have explored the Rh-catalyzed hydrogenations of a-
To test the synthetic utility of these ligands, we
1
diastereoselectivity based on H NMR analysis. The dehydroamino acid esters. The catalysts 7a,
axial chirality S was assigned to the intermediate 5 [Rh(cod)L*]BF4 (where L* is the chiral ligand 1a, b)
when a crystal suitable for X-ray diffraction was were prepared as reddish brown solid from
grown and analyzed.[15] Reduction of the nitro groups [Rh
(cod)2]BF4 and the corresponding 1a, b in di-
b
AHCTUNGTRENNUNG
a
AHCTUNGTRENNUNG
in intermediate 5 gave the chiral diamine 6 utilizing chloromethane at room temperature for 20 min. The
5% Pd/C catalyst and at a pressure of 50 atm hydro- complexes obtained were used directly in the catalytic
gen at room tempresure (99% yield). In the presence reactions.
of 4-dimethylaminopyridine (DMAP) as a hypernu-
Asymmetric hydrogenation of a-dehydroamino
cleophilic acylation catalyst, diamine 6 was readily acid esters demonstrates an efficient approach to
transformed to bisaminophosphine ligands 1a, b in access chiral amino acids and their derivatives, which
moderate yields after reactions with the correspond- are key structural elements in both natural products
ing diarylphosphine chlorides.[9]
and pharmaceuticals.[16] We initiated our studies by
Several features are highlighted in the synthetic screening catalysts 7a, b and solvent systems on the
strategy for diaminophosphine ligands. First, the low asymmetric hydrogenation of methyl 2-acetamido-3-
hindered and strong electron-withdrawing bisnitro phenylpropanoate as the model. Under optimized
groups in compound 4 facilitated the Ullmann cou- conditions, the reaction was performed at room tem-
pling reaction, giving the desired intermediate 5 in a perature under 5 atm hydrogen pressure. Both cata-
very high yield. This strategy circumvents the problem lysts were found to be effective for this hydrogena-
in our initial effort to attach bis(diethyl phosphonate) tion, giving complete conversion over 12 h with
groups in this step, which led to a relatively low oxi- 1 mol% catalyst loading. The enantioselectivities
dative homo-coupling yield.[11c] Second, the introduc- achieved in these reactions are shown in Table 1. In
tion of the synthetically flexible intermediate 6 allows the presence of the 7a complex, up to 97% ee and
for the convenient divergent incorporation of various >99% conversion were observed (Table 1, entry 2).
aryl substituents of the PAr2 moieties in the last step. The introduction of the somewhat more bulky 3,5-di-
Third, the chiral linking bridge of the 2,4-pentanediol methyl (1b) groups gave the best enantioselectivity,
tether is very simple and flexible enough for the chir- up to 98% ee in methanol (Table 1, entry 8).
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Xianfeng Sun et al.
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Table 1. Ligand and solvent screenings for the asymmetric
hydrogenation of methyl 2-acetamido-3-phenylpropanoate
8a.
Under the optimized reaction conditions, a variety
of a-dehydroamino acid esters 8a–l were examined
for hydrogenation (Table 2, entries 1–13). The ligand
1b system always shows similar or better enantioselec-
tivities than ligand 1a under the same conditions. All
the substrates (Table 2) were reduced to form chiral
aminocarboxylic acids with excellent enantioselectivi-
ties (93–98%). The electronic and steric nature of a
substituent on the phenyl ring of the substrate had
little influence on the enantioselectivity and reactivity
of the reaction. These enantiomeric excesses were
comparable or better in some cases than those ob-
tained when the similar ligand system Xyl-BDPAB or
DMBDPPABD was employed.[8g–j] In addition, hydro-
genation of the substrate 8c with a reduced catalyst
loading (ligand 1b, 0.1 mol%) still afforded the corre-
sponding product in full conversion with 96% ee.
(Table 2, entry 4).
In conclusion, a highly efficient strategy for the syn-
thesis of a series of modular and fine-tunable chiral
bisaminophosphine ligands was well established with
several remarkable features. The synthetic utility of
these ligands was explored for rhodium-catalyzed
asymmetric hydrogenations of a-dehydroamino acid
esters. Up to 98% ee values were achieved for the
enantioselective syntheses of aminocarboxylic acids
[a]
Unless otherwise noted, the reactions were carried out
with S/C=100.
All reactions were carried out under 5 atm H2 for 12 h at
[b]
room temperature.
Enantiomeric excesses were determined by chiral GC
[c]
using a Chiralsil-Val column.
Absolute configurations of the products were determined
[d]
by comparing the GC retention times with the reported
data in the literature.
Table 2. Rh-catalyzed asymmetric hydrogenation of a-dehydroamino acid esters.
[a]
[b]
[c]
[d]
Unless otherwise noted, the reactions were carried out with S/C=100; all reactions
were carried out under 5 atm H2 for 12 h at room temperature.
Enantiomeric excesses were determined by chiral GC using a Chiralsil-Val column or
chiral HPLC using Chiralcel OD-H column.
Absolute configurations of the products were determined by comparing the GC re-
tention times with the data reported in the literature.
S/C=1000.
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Enantioselective Hydrogenation of a-Dehydroamino Acid Esters
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General Procedure
To a solution of [Rh
4 mL of degassed anhydrous CH2Cl2, was added a solution
of bisaminophoshine ligand (0.016 mmol) in CH2Cl2
ACHTUGNRTEN(NUGN cod)2]BF4 (6.1 mg, 0.015 mmol) in
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1
(4 mL) at room temperature. The reaction mixture was
stirred at room temperature for 20 min before the solvent
was removed under vacuum. The resulting complex was
used for hydrogenation without further purification. The re-
sulting complex was dissolved in degassed MeOH (15 mL)
in the glovebox and was equally distributed into 15 vials. To
the catalyst solution was added substrate (0.1 mmol). The
vials were transferred into an autoclave, and the autoclave
was purged with H2 (5 atm, for three times) and charged
with H2 (5 atm). After stirring at room temperature for 12 h,
the H2 was carefully released. The reaction solution was pu-
rified on a silica gel column to give the corresponding hy-
drogenation product, which was then directly analyzed by
chiral GC or chiral HPLC to determine the enantiomeric
excess.
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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 Mr. R. Davis at Albany Molecular Research Inc. in the
preparation of the manuscript is also gratefully acknowl-
edged.
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