Rigid P-chiral phosphine ligands with tert -butylmethylphosphino groups for rhodium-catalyzed asymmetric hydrogenation of functionalized alkenes

Article abstract of DOI:10.1021/ja209700j

Both enantiomers of 2,3-bis(tert-butylmethylphosphino)quinoxaline (QuinoxP*), 1,2-bis(tert-butylmethylphosphino)benzene (BenzP*), and 1,2-bis(tert-butylmethylphosphino)-4,5-(methylenedioxy)benzene (DioxyBenzP*) were prepared in short steps from enantiopure (S)- and (R)-tert-butylmethylphosphine-boranes as the key intermediates. All of these ligands were crystalline solids and were not readily oxidized on exposure to air. Their rhodium complexes exhibited excellent enantioselectivities and high catalytic activities in the asymmetric hydrogenation of functionalized alkenes, such as dehydroamino acid derivatives and enamides. The practical utility of these catalysts was demonstrated by the efficient preparation of several chiral pharmaceutical ingredients having an amino acid or a secondary amine component. A rhodium complex of the structurally simple ligand BenzP* was used for the mechanistic study of asymmetric hydrogenation. Low-temperature NMR studies together with DFT calculations using methyl α-acetamidocinnamate as the standard model substrate revealed new aspects of the reaction pathways and the enantioselection mechanism.

Full text of DOI:10.1021/ja209700j

Article
pubs.acs.org/JACS
Rigid P-Chiral Phosphine Ligands with tert-Butylmethylphosphino
Groups for Rhodium-Catalyzed Asymmetric Hydrogenation of
Functionalized Alkenes
Tsuneo Imamoto,*,†,‡ Ken Tamura,† Zhenfeng Zhang,† Yumi Horiuchi,† Masashi Sugiya,†
Kazuhiro Yoshida,‡ Akira Yanagisawa,‡ and Ilya D. Gridnev*,§
†Organic R&D Department, Nippon Chemical Industrial Co., Ltd., Kameido, Koto-ku, Tokyo 136-8515, Japan
‡Department of Chemistry, Graduate School of Science, Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
§Department of Applied Chemistry, Graduate School of Science and Engineering, Tokyo Institute of Technology, Ookayama,
Meguro-ku, Tokyo 152-8552, Japan
S
* Supporting Information
ABSTRACT: Both enantiomers of 2,3-bis(tert-butylmethylphosphino)-
quinoxaline (QuinoxP*), 1,2-bis(tert-butylmethylphosphino)benzene
(BenzP*), and 1,2-bis(tert-butylmethylphosphino)-4,5-(methylenedioxy)-
benzene (DioxyBenzP*) were prepared in short steps from enantiopure
(S)- and (R)-tert-butylmethylphosphine−boranes as the key intermedi-
ates. All of these ligands were crystalline solids and were not readily
oxidized on exposure to air. Their rhodium complexes exhibited excellent
enantioselectivities and high catalytic activities in the asymmetric hydro-
genation of functionalized alkenes, such as dehydroamino acid derivatives and enamides. The practical utility of these
catalysts was demonstrated by the efficient preparation of several chiral pharmaceutical ingredients having an amino acid or a
secondary amine component. A rhodium complex of the structurally simple ligand BenzP* was used for the mechanistic
study of asymmetric hydrogenation. Low-temperature NMR studies together with DFT calculations using methyl α-
acetamidocinnamate as the standard model substrate revealed new aspects of the reaction pathways and the enantioselection
mechanism.
DIPAMP developed by Knowles et al. in 1975.12a This ligand
has played a very important role in the development of
INTRODUCTION
Chiral phosphine ligands have played an important role in
■
asymmetric catalysis, and quite notable is the fact that it was
transition-metal-catalyzed asymmetric reactions, and an enor-
employed for the first time in industry for the production of
mous number of ligands have been designed and synthesized
L-DOPA by rhodium-catalyzed asymmetric hydrogenation.12c,d
Unfortunately, despite the landmark success of the discovery of
DIPAMP, relatively little attention had been paid to this class of
P-chiral phosphine ligands for more than 20 years, mainly
because of synthetic difficulty and apprehension about the
possible stereomutation at P-stereogenic centers.
over the past four decades.1 Owing to unrelenting effort
including the development of new catalytic asymmetric
transformations, many chiral ligands have been proven to
exhibit excellent enantioselectivities and some outstanding
ligands have been employed in the industrial production of
useful optically active compounds.2,3 However, there are no
“almighty” ligands, and hence, the exploration of more efficient
and widely applicable chiral phosphine ligands is still a vital
research topic in the field of asymmetric catalysis.4
Chiral phosphine ligands are largely classified into two
categories. One category consists of ligands with chirality in
their backbones. Representative examples are DIOP,5 CHIR-
APHOS,6 BINAP,7 DuPHOS,8 Josiphos,9 SEGPHOS,10 and
SDP,11 in which the same two substituents, aryl groups in most
cases, on the phosphorus atom are diastereotopic, influenced by
stereogenic carbon centers or chirality based on the axial or
planar molecular framework. Another category consists of chiral
phosphine ligands exemplified by DIPAMP,12 BisP*,13
MiniPHOS,14 TangPhos,15 Trichickenfootphos,16 DuanPhos,17
SMSPhos,4g,q,r and ZhangPhos,4v all of which possess their
chiral centers at phosphorus atoms. The most prominent is
We have long been interested in furthering the potential
utility of P-chiral phosphine ligands and, to this end, have tried
to explore new and efficient methods for their synthesis. In our
initial approach published in 1985, we used phosphine−boranes
having a methyl group, where the boranato group of the
phosphine−boranes was considered to be a protecting group
of phosphine and also an activating group to facilitate the
deprotonation from the methyl group.18 Consequently, the
usefulness of the protocol was proven in the synthesis of
DIPAMP and its analogous ligands.18,19 In 1998, we prepared
for the first time a P-chiral bidentate trialkylphosphine ligand,
(S,S)-1,2-bis(tert-butylmethylphosphino)ethane ((S,S)-t-Bu-BisP*),
Received: October 15, 2011
Published: December 14, 2011
© 2011 American Chemical Society
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from tert-butyl(dimethyl)phosphine−borane by utilizing our
phosphine−borane methodology and Evans’ procedure that
employed (−)-sparteine/s-BuLi as the enantioselective depro-
tonation reagent.13,20 A similar ligand, (R,R)-bis(tert-
butylmethylphosphino)methane ((R,R)-t-Bu-MiniPHOS),
was also prepared in the following year.14a These two ligands
exhibited almost perfect enantioselectivities in the rhodium-
catalyzed asymmetric hydrogenation of some α-dehydroamino
acids and related substrates, although the molecular structures of
the catalysts are quite simple. Nevertheless, these ligands have
seen little use in asymmetric catalyses because they are waxy or
oily air-sensitive substances and cannot be conveniently handled
in air. Another problem is that only single enantiomer ligands
are obtained by the use of naturally occurring (−)-sparteine
and the opposite enantiomers cannot be prepared by the
straightforward procedure.21,22
Based on the facts mentioned above, we intended to prepare
new ligands that are practically useful for various catalytic
asymmetric transformations. The newly designed ligands are
2,3-bis(tert-butylmethylphosphino)quinoxaline (QuinoxP*),
1,2-bis(tert-butylmethylphosphino)benzene (BenzP*), and
1,2-bis(tert-butylmethylphosphino)-4,5-(methylenedioxy)-
benzene (DioxyBenzP*). A common feature of these ligands
is that two stereochemically equivalent tert-butylmethylphosphino
groups are attached to the 1,2-positions of the aryl group. This
molecular framework would lead to the formation of a
C2-symmetric five-membered chelate that is more rigid than
the metal complex of t-Bu-BisP* and hence would further
enhance enantioselectivity. The electron-attracting quinoxaline
and the electron-donating (methylenedioxy)benzene backbones
may affect the chemical properties of the ligands as well as the
catalytic activity and the enantioselectivity. The anticipated
electronic effects have attracted our interest and inspired us to
prepare these ligands.23 Herein we report the preparation of these
ligands and their application to the rhodium-catalyzed asymmetric
hydrogenation of prochiral functionalized alkenes.
Scheme 1. Preparation of (S)- and (R)-tert-
Butylmethylphosphine−Boranes from tert-Butylphosphines
a
a
Reagents and conditions: (a) (i) MeI, (ii) NaBH4; (b) (i) n-BuLi, (ii)
(−)-bornyl chloroformate; (c) KOH, H2O/MeOH; (d) (S)-PhCH-
(Me)NCO, n-BuLi (10 mol %); (e) KOH, H2O/THF; (f) (i) n-BuLi,
(ii) Br(CH2)2Br, (iii) LiAlH4.
in high yield. This racemate was reacted with n-BuLi and
(−)-bornyl chloroformate and the resulting diastereomeric
mixture was recrystallized to give diastereomerically pure 2.
On the other hand, the reaction of 1 with (S)-1-phenylethyl
isocyanate, followed by recrystallization, afforded diastereo-
merically pure 3. Compounds 2 and 3 were subjected to
hydrolysis to afford (S)-1 and (R)-1, respectively, in satis-
factory yields.
We then looked into the possibility of converting the single
enantiomer secondary phosphine−borane into its opposite
enantiomer. After several trials, it was found that (S)-1 was
converted into (R)-1 in 90% yield and 97% enantioselectivity
on successive treatments with n-BuLi, 1,2-dibromoethane, and
LiAlH4 in ether at low temperature.22 This result indicates that
the reverse transformation is also possible and hence, we can
supply (S)-1 or (R)-1 from each opposite enantiomer.
Through the reactions mentioned above, we were able to
obtain sufficient quantities of both enantiopure secondary
phosphine−boranes (S)-1 and (R)-1 for the preparation of
QuinoxP*, BenzP*, and DioxyBenzP*.
Synthesis of P-Chiral Phosphine Ligands and Their
Rhodium Complexes. 2,3-Bis(tert-butylmethylphosphino)-
quinoxaline (QuinoxP*). Our initial trial for the synthesis of
QuinoxP* was conducted with the use of (S)-1. The method is
shown in Scheme 2. The overall reaction sequence consists of
The mechanism of rhodium-catalyzed asymmetric hydro-
genation is one of our continuing research subjects.24−26 We
have studied the mechanism by using a rhodium complex of the
structurally simple BenzP* and methyl α-acetamidocinnamate
(MAC) as a typical probing substrate with the expectation that
unprecedented mechanistic aspects will be revealed by NMR
studies coupled with DFT calculations.
a
Scheme 2. Preparation of (R,R)-QuinoxP* from (S)-1
RESULTS AND DISCUSSION
■
a
Preparation of Enantiopure (S)- and (R)-tert-Butylme-
thylphosphine−Boranes. In order to prepare the target li-
gands, we needed both enantiopure tert-butylmethylphosphine−
boranes (S)-1 and (R)-1. After searching for protocols that
are capable of preparing both enantiomers (S)-1 and (R)-1 in
large scale, we eventually used diastereomerically pure (RP)-
((−)-bornyloxy)(tert-butyl)methylphosphine−borane (2) and
(SP,S)-tert-butyl(methyl)(1-phenylethylcarbamoyl)phosphine−
borane (3) as the intermediates (Scheme 1).22 Here, tert-
butylphosphine was reacted successively with iodomethane and
NaBH4 to give racemic tert-butylmethylphosphine−borane (1)
Reagents and conditions: (a) (i) n-BuLi, THF, −80 °C, (ii) 2,3-
dichloroquinoxaline, −80 °C to rt, (iii) TMEDA, rt.
three steps: (1) lithiation of (S)-1 with n-BuLi, (2) addition/
elimination reaction with 2,3-dichloroquinoxaline, and (3)
deboranation with tetramethylethylenediamine (TMEDA). It
should be noted that the three steps were carried out in one pot
and the product QuinoxP* was obtained in 80% yield as an
orange crystalline solid.27 Recrystallization of the crude product
from methanol gave pure (R,R)-QuinoxP*. The opposite
enantiomer ligand (S,S)-QuinoxP* was also prepared by the
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same method but using (R)-1. Notable is that crystalline
QuinoxP* was neither oxidized nor epimerized at the
stereogenic phosphorus atoms on exposure to air at room
temperature for more than 1 month.28
1,2-Bis(tert-butylmethylphosphino)benzene (BenzP*).
Ligand BenzP* possessing an ortho-phenylene backbone has
long caught our attention because it looks quite simple and
structurally fundamental. We have expected that the ligand
would form an imposed five-membered chelate ring and the
steric contrast between the tert-butyl group and the methyl
group would induce excellent enantioselectivities in various
asymmetric catalyses.
more than one week. This operationally convenient property of
BenzP* is potentially useful for various asymmetric catalyzes.31
1 , 2 - B i s ( t e r t - b u t y l m e t h y l p h o s p h i n o ) - 4 , 5 -
(methylenedioxy)benzene (DioxyBenzP*). Our first
choice for the preparation of DioxyBenzP* was above-
mentioned reaction sequence, using 1,2-dibromo-4,5-
(methylenedioxy)benzene and (S)-1 as the starting materials.
However, the first step resulted in the formation of a complex
reaction mixture containing a small amount of desired
compound 8 and undesired 9 (Scheme 4).
a
Scheme 4. Formation of Compounds 8 and 9
Our initial attempt to prepare BenzP* was conducted
through transition-metal-catalyzed cross-coupling reactions of
o-dibromobenzene or o-diiodobenzene with (S)-1 in the
presence of a base. Unfortunately, in most cases, monosub-
stituted compounds were produced in low to moderate yields
and the desired disubstituted compound was not isolated at all.
Subsequent trials led to the finding of a route to the target
BenzP* (Scheme 3). The reaction of the lithium derivative of
a
Reagents and conditions: (a) (i) n-BuLi, THF, −80 °C, (ii) 1,2-
dibromo-3,4-(methylenedioxy)benzene, −80 °C ∼ 0 °C.
a
Scheme 3. Preparation of (R,R)-BenzP* from (S)-1
The use of 1,2-diiodo-4,5-(methylenedioxy)benzene signifi-
cantly improved the reaction to provide the desired compound
10 in 58% yield (Scheme 5). This compound was reacted
a
Scheme 5. Preparation of (R,R)-DioxyBenzP*
a
Reagents and conditions: (a) (i) n-BuLi, THF, −80 °C, (ii)
o-C6H4Br2, −80 °C ∼ 0 °C; (b) DABCO, THF, reflux; (c) s-BuLi,
−80 °C; (d) t-BuPCl2, −80 °C ∼ 0 °C; (e) MeMgBr, 0 °C ∼ rt.
(S)-1 with o-dibromobenzene afforded (R)-(2-bromophenyl)-
(tert-butyl)methylphosphine−borane (4) as a crystalline
compound with complete retention of configuration at the
phosphorus atom in 65% yield.29,30 This compound was
reacted successively with 1,4-diazabicyclo[2.2.2]octane
(DABCO), sec-butyllithium, tert-butyldichlorophosphine, and
methylmagnesium bromide to give desired ligand (R,R)-
BenzP* in 38% yield. It should be noted that these four
reaction steps were carried out in one pot without having to
isolate intermediates 5−7 and fortunately, (R,R)-BenzP* was
readily separated as a crystalline solid from other byproducts,
such as a meso-diphosphine isomer. The overall yield from (S)-
1 may be unsatisfactory (25%), but one great merit of this
process is the concise reaction pathway with no requirement of
chromatography. In the same manner, the counter enantiomer
ligand (S,S)-BenzP* was prepared from (R)-1.
a
Reagents and conditions: (a) (i) s-BuLi (3 equiv), −80 °C, (ii) 1,2-
diiodo-4,5-(methylenedioxy)benzene, (iii) I2, THF, −80 °C; (b) (i)
DABCO, THF, reflux, (ii) i-PrMgCl•LiCl; (c) (i) t-BuPCl2, (ii)
MgMgBr, (iii) BH3•THF; (d) DABCO, THF, reflux.
subsequently with DABCO and i-PrMgCl·LiCl32,33 to form
organomagnesium intermediate 11, which was further reacted
with tert-butyldichlorophosphine and methylmagnesium bro-
mide. The reaction mixture was worked-up in a manner similar
to the preparation of BenzP*, but the product (R,R)-
DioxyBenzP* did not crystallize out from the solution
containing the other byproducts. We next tried to isolate the
ligand as a borane adduct by the addition of borane−THF
complex to the reaction mixture. Through this procedure and
subsequent column chromatography, we obtained monoborane
adduct 12 as an air-stable crystalline solid,34 and this was finally
converted to (R,R)-DioxyBenzP* on treatment with DABCO
in refluxing THF (Scheme 5).
We anticipated the high sensitivity of BenzP* to air as the
electron density at the phosphorus atom was considered to be
higher than that of QuinoxP*. Contrary to this anticipation,
crystalline BenzP* was not oxidized when exposed to air for
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In a similar manner, (S,S)-DioxyBenzP* was prepared from
(R)-1 and 1,2-diiodo-4,5-(methylenedioxy)benzene. Thus
obtained DioxyBenzP* was a colorless crystalline solid. This
ligand is not so stable in air compared with QuinoxP* and
BenzP*, but can be handled in air for as long as a few hours.
Rhodium Complexes of QuinoxP*, BenzP*, and
DioxyBenzP*. The above-mentioned P-chiral phosphine
ligands were reacted with cationic rhodium diene complexes
([Rh(cod)2]SbF6 (cod: 1,5-cyclooctadiene), [Rh(cod)2]PF6,
[Rh(cod)2]BF4, ([Rh(nbd)2]SbF6, (nbd: norbornadiene), and
[Rh(nbd)2]BF4) to prepare catalyst precursors for asymmetric
hydrogenation. Among these diene complexes, [Rh(cod)2]SbF6
was found to be most suitable for the preparation of the catalyst
precursors. Thus, [Rh(QuinoxP*)(cod)]SbF6, [Rh(BenzP*)-
(cod)]SbF6, and [Rh(DioxyBenzP*)(cod)]SbF6 were obtained
as wine red or orange crystalline solids in good to high yields.
The rhodium complex [Rh((R,R)-BenzP*)(nbd)]SbF6 for
mechanistic study was also prepared by reacting (R,R)-
BenzP* with [Rh(nbd)]SbF6, the latter of which was generated
in situ by mixing [RhCl(nbd)]2 and silver hexafluoroantimo-
nate in acetone.
Figure 2. ORTEP drawing of [Rh((R,R)-BenzP*)(cod)]SbF6. All
hydrogen atoms and counteranion (SbF6) are omitted for clarity.
The molecular structures of [Rh(QuinoxP*)(cod)]SbF6 and
[Rh(BenzP*)(cod)]SbF6 were determined by single-crystal X-ray
analysis. Respective ORTEP drawings are shown in Figures 1 and 2.
Figure 3. ORTEP drawing of [Rh((S,S)-BisP*)(nbd)]BF4. All
hydrogen atoms and counteranion (BF4) are omitted for clarity.
the quasi-axial positions. It is apparent that QuinoxP* and
BenzP* form more rigid rhodium complexes owing to the aryl
backbones than t-Bu-BisP* having a two-methylene backbone.
In addition, the tert-butyl groups shield the north−northwest-
ern area of the second quadrant and the south−southeastern
area of the fourth quadrant. These strictly imposed asymmetric
environments lead us to anticipate higher enantioselectivities
than the use of the rhodium complex of t-Bu-BisP*.
Rhodium-Catalyzed Asymmetric Hydrogenation of
Functionalized Alkenes. The enantioinduction ability and
the catalytic activity of the rhodium complexes of QuinoxP*,
BenzP*, and DioxyBenzP* were examined in the asymmetric
hydrogenation of prochiral functionalized alkenes. We focused
our attention on the hydrogenation of α- and β-dehydroamino
acids derivatives and enamides. This is because they are three
fundamental sets of nitrogen-functionalized alkenes for
asymmetric hydrogenation and the produced optically active
compounds feature versatile utility in industry as well as in
many scientific areas.35
Figure 1. ORTEP drawing of [Rh((R,R)-QuinoxP*)(cod)]SbF6. All
hydrogen atoms and counteranion (SbF6) are omitted for clarity.
The two structures closely resemble each other, particularly for
the asymmetric environment around rhodium and phosphorus
atoms. The five-membered chelate rings are slightly distorted
from the P1−Rh−P2 plane. Thus, the dihedral angles between
the P1−Rh−P2 plane and the backbone C−C bond of
QuinoxP*-Rh and BenzP*-Rh complexes are 7.2° and 12.0°,
respectively. The front views and the side views clearly show
that the aromatic rings are inclined from the plane to form
δ-type chelate structures, whereby the bulky tert-butyl groups
occupy the quasi-axial positions and the methyl groups are
located at the quasi-equatorial positions. It is interesting to
compare these crystal structures with that of the rhodium
complex of (S,S)-bis(tert-butylmethylphosphino)ethane (t-Bu-
BisP*).13,14b Figure 3 shows three ORTEP views of [Rh((S,S)-
t-Bu-BisP*)(nbd)]BF4. In contrast to the former complexes,
this complex forms a λ-type chelate structure with a larger
dihedral angle (27.0°) between the P1−Rh−P2 plane and the
backbone C−C bond, where the tert-butyl groups occupy the
quasi-equatorial positions and the methyl groups are located at
1. Asymmetric Hydrogenation of α-Dehydroamino Acid
Derivatives. The rhodium-catalyzed asymmetric hydrogenation
of α-dehydroamino acid derivatives is one of the most
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Table 1. Asymmetric Hydrogenation of α-Dehydroamino Acid Derivatives
a
b
All reactions were carried out in methanol at room temperature, unless otherwise noted. All reactions were completed under the conditions, unless
c
1
otherwise stated. The conversions were determined by H NMR. The reaction was carried out in dichloromethane.
frequently studied asymmetric catalyses. One major reason is
that the reaction offers a straightforward way for the synthesis
of optically active α-amino acids from inexpensive starting
materials. Another reason is that this hydrogenation is utilized
as a probing reaction to test the enantioinduction ability of
newly synthesized chiral phosphine ligands.
With three sets of rhodium complexes in hand, we at first
examined their enantioinduction abilities in the hydrogenation
of α-dehydroamino acid derivatives. The results are summa-
rized in Table 1.
Entries 1−9 show the results obtained by the use of a typical
probing substrate, methyl α-acetamidocinnamate (MAC)
(13a). The hydrogenation with S/C = 1000 under 3 atm H2
pressure at room temperature was completed within 0.3−0.5 h
to produce the corresponding product with 99.9% ee (entries 1,
2, 4, 5, 7, and 8). Both enantiomer catalysts afforded the same
ee's, proving that they have the same catalytic efficiencies. The
hydrogenation with S/C = 10000 under 5 atm H2 pressure was
also examined. The use of QuinoxP*-Rh complex resulted in a
low chemical yield under these conditions, whereas the ee of
the product was quite high (99.7%) (entry 3). Complete
conversion was observed when BenzP*-Rh and DioxyBenzP*-
Rh were used; BenzP*-Rh afforded the product with 99.8% ee
after 5 h (entry 6) whereas DioxyBenzP*-Rh required a longer
reaction time to give the product with significantly lower ee
(95.1%) (entry 9). β-Unsubstituted derivative 13b was also
hydrogenated (entries 10−15). Except for entry 15, the
reactions proceeded rapidly to yield the product with 99.8−
99.9% ee, even when 10000 S/C ratio was employed.
Application to the hydrogenation of 13c leading to the
precursor to L-DOPA provided notable results. All the three
catalysts were quite efficient to give products with 99.9% ee
(entries 16−18). These results, together with the catalytic
efficiencies, are favorable compared with the highest values
hitherto reported for this transformation.3a Compound 13d was
also readily subjected to hydrogenation to give optically active
2-naphthylalanine, which is a versatile precursor to such
pharmaceutically important compounds as SDZ NKT 343, a
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potent human NK1 tachykinin receptor antagonist (entries 19
and 20).36,37 Free α-dehydroamino acids 13e,f were also readily
reduced under similar conditions (entries 21−26). The
enantioinduction abilities were tested also for the hydro-
genation of compounds possessing a 2-furyl or a 2-pyrrolyl
group (entries 27−34). The reactions were completed in
methanol under 3 atm H2 pressure to give products with
considerably high enantioselectivities when 200 S/C ratio was
employed. The reactions with S/C = 1000 in dichloromethane
resulted in incomplete conversion (entries 29 and 33).
2. Hydrogenation of β-Dehydroamino Acids Derivatives.
The rhodium-catalyzed asymmetric hydrogenation of β-
dehydroamino acid derivatives is one of the most efficient
methods for the production of chiral β-amino acids, and
considerable effort has been made in this area.38 In most cases,
the hydrogenation of (E) derivatives gives rise to high
enantioselectivities compared with that of (Z) derivatives; the
latter reactions require higher H2 pressure and/or a longer
reaction time to yield products with lower enantioselectivities,39
while in some cases, comparatively high enantioselectivities are
observed.4n,v,40
We employed rhodium catalysts in the hydrogenation of
several β-substituted β-(acetylamino)acrylates 14a−h. The
results are shown in Table 2. The hydrogenation of methyl
(E)-3-acetamido-2-butenoate ((E)-14a) in the presence of
0.1 mol % (R,R)-QuinoxP*-Rh under 3 atm H2 pressure was
completed within 1 h to give the product with 99.9% ee
(entry 1). The corresponding (Z)-isomer was also smoothly
subjected to hydrogenation under the same conditions to give
the product with slightly lower ee (99.0%) (entry 2). Use of
(R,R)-BenzP*-Rh provided almost the same results (entries 3
and 4). A 1:1 mixture of (E)-14a and (Z)-14a was also
subjected to hydrogenation to show the mean ee value (98.7%)
(entry 5) and lower catalyst loading (S/C = 5000) resulted in
slightly lower ee (97.9%) (entry 6). (R,R)-DioxyBenzP*-Rh
was also effective for both (E)-14a and (Z)-14a, giving the
product with 99.5% ee and 98.5% ee, respectively (entries 7 and
8). Compound (E)-14b (R1 = Pr) was similarly hydrogenated
Table 2. Asymmetric Hydrogenation of β-Dehydroamino Acid Derivatives
a
b
All reactions were carried out in methanol at room temperature. All reactions were completed under the conditions, unless otherwise stated. The
c
d
e
1
conversions were determined by H NMR. The reaction was carried out in dichloromethane. In THF. In ethyl acetate.
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to yield the product with enantioselectivities of 99.1−99.9%,
and its (Z)-isomer (Z)-14b underwent hydrogenation to yield
the product with slightly lower selectivities (94.0−97.6%).
Compound (Z)-14c (R1 = i-Pr) was hydrogenated to furnish
the product with significantly lower enantioselectivities (86−
93.1% ee), whereas (R,R)-DioxyBenzP*-Rh gave the product
that had the highest selectivity (93.1% ee) (entries 15−17). It
should be noted that these results are superior to previously
reported ones (MalPHOS: 69% ee;39d Me-DuPHOS: 4% ee;39d
Et-FerroTANE: 31% ee;40c Trichickenfootphos: 69% ee40d).
The asymmetric hydrogenation of aryl-substituted (Z)-β-
dehydroamino acid esters ((Z)-14d−h) took place under 3−5
atm H2 pressure. Model substrate (Z)-14d was rapidly
converted into the corresponding β-amino acid derivative; the
use of QuinoxP* gave the corresponding product with the
highest ee (98.1%) whereas DioxyBenzP* afforded the pro-
duct with the lowest ee (95.4%) (entries 18−20). Similarly,
p-methoxyphenyl- or p-fluorophenyl-substituted compounds
((Z)-14e,f) were hydrogenated with complete conversion and
excellent enantioselectivities (entries 21−26). In sharp contrast,
3,5-dichlorophenyl-substituted derivative (Z)-14g furnished the
product with unexpectedly low ee under the same conditions in
the presence of QuinoxP*-Rh (entry 27). Changing the solvent
from methanol to dichloromethane improved the enantio-
selectivity from 59% ee to 73% ee (entry 28). A similar result
was obtained when BenzP*-Rh was used (entry 30). When
DioxyBenzP*-Rh was employed, high enantioselectivity was
observed, and in dichloromethane 90% ee was achieved (entries
31 and 32). Further trials that involved changing of the solvent
to THF and ethyl acetate resulted in rather lower
enantioselectivities (entries 33 and 34). On the other hand, the
hydrogenation of ortho-substituted compound (Z)-14h pro-
vided excellent results (entries 35−37). Thus, the enantiose-
lectivity (95.5% ee) obtained by the use of (R,R)-BenzP*-Rh is
comparable to the previously reported highest level selectivities
(e.g., Binapine: >99% ee;40c ZhangPhos: 92% ee4v).
3. Hydrogenation of α-Substituted Enamides. Optically
active secondary amines are frequently used as resolving agents,
chiral auxiliaries, and intermediates in the synthesis of a wide
range of biologically active compounds. The asymmetric hydro-
genation of α-substituted enamides is considered to be one of
the efficient preparative routes to this class of compounds, and
many chiral phosphine ligands have been used for this
transformation. Although very high enantioselectivities have
been achieved by the use of such ligands as DuPHOS,41 BPE,41
t-Bu-BisP*,42 BDPMI,43 TangPhos,15 R-SMS-Phos,4g,q,r and
BIBOP,4n more efficient and practically useful methods with
lower catalyst loading as well as mild reaction conditions are
urgently required especially for practical applications.
We tested the applicability of the above-mentioned rhodium
complexes in the asymmetric hydrogenation of some
representative α-substituted enamides. The results are listed
in Table 3.
The hydrogenation of α-arylenamides 15a−c was run in
methanol at room temperature in the presence of 0.1 mol %
rhodium complex under 3 or 5 atm H2 pressure. In the case of
N-(1-phenylvinyl)acetamide (15a), the reaction times and
enantioselectivities differed significantly depending on the
Table 3. Asymmetric Hydrogenation of α-Substitiuted Enamides
a
b
All reactions were carried out in methanol at room temperature, unless otherwise stated. All reactions were completed under the conditions, unless
c
1
otherwise stated. The conversions were determined by H NMR. The reaction was carried out in dichloromethane.
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ligand (entries 1−3); when QuinoxP*-Rh complex was used,
the reaction was completed within 1.5 h and the product had
excellent enantioselectivity (99.4% ee), whereas BenzP*-Rh
and DioxyBenzP*-Rh provided the product with 92.9% ee and
90% ee, respectively. Analogous results were obtained in the
hydrogenation of N-(1-(2-naphthyl)vinyl)acetamide (15b). In
contrast, all three complexes showed high catalytic efficiencies
in the hydrogenation of N-(1-(4-nitrophenyl)vinyl)acetamide
(15c) (entries 7−9).
Scheme 6. Asymmetric Hydrogenation of α-Dehydroamino
Acid Derivative 19
Compound 15d, which is an enamide having a bulky tert-
butyl group at α-position, was readily subjected to hydro-
genation to give a product with more than 95% ee (entries 10−
12). Note that in this case, an (S)-configuration product was
formed, in contrast to the hydrogenation of α-arylenamides that
led to (R)-products. The dramatic difference in stereochemical
outcome in this kind of reaction was previously observed when
Me-DuPHOS or t-Bu-BisP* was used,41b,42 and the opposite
enantioselection mechanisms were explained in terms of steric
and electronic effects.42
Cyclic enamides 16 and 17 were also used as probing
substrates. Compared to acyclic enamides, these enamides are
known to be reduced under high H2 pressure and products with
excellent enantioselectivities are hardly obtained except for
a few examples.35a,b The hydrogenation in the presence of
0.5 mol % catalyst required 20 atm H2 pressure and 18−19 h to
complete, and the resulting products had enantiomeric excesses
of 33−91.7% (entries 13−19). These ee values are comparable
to most of the reported ones, but are significantly lower than
the highest values (98−>99% ee) obtained by the use of Me-
BPE or Me-PennPhos.41b,44
β-Keto enamides are useful prochiral compounds for the
preparation of optically active β-amino ketones and 1,3-
aminoalcohols.45,46 We tested the utility of our rhodium com-
plexes for the enantioselective synthesis of β-amino ketone
using compound 18 as the standard substrate. As shown in entries
20−22, BenzP*-Rh and DioxyBenzP*-Rh provided 3-acetylamino-
1-phenyl-1-butanone with 98.6% ee, which is comparable to the
result obtained by the use of DuanPhos (96% ee).45
Preparation of Chiral Building Blocks for the
Production of Optically Active Pharmaceuticals. As
described above, the three rhodium complexes of QuinoxP*,
BenzP*, and DioxyBenzP* were found to be highly efficient
catalyst precursors for the asymmetric hydrogenation of α- and
β-dehydroamino acid derivatives and enamides. On the basis of
available data, we next employed these complexes for the
preparation of chiral ingredients for several important pharma-
ceuticals in order to examine the practical utility of the catalysts.
At first, we focused our attention on the preparation of an
optically active α-amino acid that has yet to be satisfactorily
prepared with existing methods. As the target compound, (S)-
2′,6′-dimethyltyrosine (21) was chosen because this unnatural
amino acid is used as a component of the δ-opioid antagonist
Dmt-Tic pharmacophore and its synthesis via the rhodium-
catalyzed asymmetric hydrogenation of methyl (Z)-2-acetami-
do-3-(4-acetoxy-2,6-dimethylphenyl)-2-propenoate (19) to 20
was not achieved with excellent enantioselectivitity due to the
sterically congested nature of the prochiral alkene ((R,R)-
DIPAMP: S/C = 100, H2 4 atm, ethyl acetate, 60 °C, 24 h, 92%
ee;47 (S,S)-Et-FerroTANE: S/C = 500, H2 5 atm, ethyl acetate,
60 °C, 16 h, 93% ee48). Our results are shown in Scheme 6.
The initial screening reactions using DioxyBenzP* in ethyl
acetate, THF, or methanol resulted in full conversion, but the
enantioselectivities were disappointingly low. In contrast, the
reaction in dichloromethane remarkably improved the ee to
98.2%. BenzP*-Rh provided the product with similarly high ee
(98.7%). Use of QuinoxP* in ethyl acetate gave the product
with higher ee (84%) than the use of DioxyBenzP* (68% ee).
The reaction using QuinoxP*-Rh with S/C = 200 in
dichloromethane afforded the product with 99.2% ee. Lowering
the catalyst loading to 0.1 mol % also enabled full conversion
into the product without any decrease of the enantioselectivity.
These results indicate the potential utility of this rhodium-
catalyzed hydrogenation for the production of this target amino
acid and related substrates.
Chiral β-amino acid derivatives are useful building blocks for
the synthesis of biologically active compounds, such as β-
peptides, β-lactam antibiotics, and taxol derivatives. In order to
test the practical utility of our rhodium catalysts in the
preparation of β-amino acid building blocks, we examined the
asymmetric hydrogenation of a β-dehydroamino acid derivative
23 to prepare compound 24, which is used for the synthesis of
VLA-4 antagonist S9059 (22).49 Similarly to the hydrogenation
reactions mentioned above, the hydrogenation in the presence
of 0.1 mol % catalyst under 3 atm H2 pressure proceeded
smoothly with full conversion within 1 h to provide compound
24 with excellent ee of up to 97.9% (Scheme 7). The high
efficiency together with the excellent enantioselectivitity offers a
valuable synthetic tool for the production of this chiral building
block.
Schemes 8−11 illustrate four examples of the preparation of
chiral secondary amine components of commercially available
drugs or potentially useful compounds as pharmaceuticals.
Scheme 8 shows the preparation of compound 26, a precursor
of acetylcholinesterase inhibitor SDZ-ENA-713 (27).50 The
asymmetric hydrogenation of enamide 25 using (S,S)-
QuinoxP*-Rh or (S,S)-BenzP*-Rh with S/C = 1000 under 3
atm H2 pressure proceeded rapidly at room temperature to give
26 with 99.4% ee and 93.9% ee, respectively. The result
obtained using (S,S)-QuinoxP*-Rh was superior to the previous
approach that used (S,S)-t-Bu-BisP*, which afforded the same
product with 97% ee.42
Compound 28 is CGP-55845, a GAVA-B antagonist that has
been investigated by Novartis as a potential treatment for
epilepsy.51 Previously, Harrison and Meek studied the
preparation of a potential intermediate to 28 and carried out
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Scheme 7. Asymmetric Hydrogenation of β-Dehydroamino
Scheme 10. Asymmetric Hydrogenation of Enamide 32
Acid Derivative 23
Scheme 8. Asymmetric Hydrogenation of Enamide 25
Scheme 11. Asymmetric Hydrogenation of Enamide 34
Scheme 9. Asymmetric Hydrogenation of Enamide 29
the product with 98.7% enantioselectivity. Lowering the catalyst
loading to S/C = 10000 was also examined under 5 atm H2
pressure and after 30 h, we obtained the product with 97.7% ee
in 90% yield. These results compare favorably with the
previously reported ones and indicate the potential utility for
the production of intermediate 30.
Casopitant (31) is a potent neurokinin 1 (NK1) receptor
antagonist developed by GlaxoSmithKline and its mesylate is
effective for the treatment of chemotherapy-induced nausea
and vomiting.53 This compound contains an (R)-bis-
(trifluoromethyl)phenylethylamine component that is used as
a chiral building block for the manufacture of this drug. We
tried to prepare building block 33 via the asymmetric
hydrogenation of enamide 32. The results are described in
Scheme 10. The hydrogenation using QuinoxP*-Rh and
BenzP*-Rh complexes proceeded rapidly to give the product
in 99.9% ee, whereas use of DioxyBenzP*-Rh resulted in
slightly decreased enantioselectivity (98.1%). It should be
noted that the hydrogenation in the presence of QuinoxP*-Rh
with S/C = 10000 proceeded under 5 atm H2 pressure to lead
to full conversion after 20 h without any decrease of
enantioselectivity. The almost perfect enantioselectivity and
the asymmetric hydrogenation of 29 in the presence of (S,S)-
Et-DuPhos-Rh (S/C = 5000) in methanol at 40 °C under 10
atm H2 pressure to furnish 30 within 80 min with excellent
enantioselectivity (97% ee).52 We examined the same trans-
formation using rhodium complexes of (S,S)-QuinoxP* and
(S,S)-BenzP*. The results are included in Scheme 9. It should
be noted that the hydrogenation using QuinoxP*-Rh with S/C =
1000 at room temperature was completed within 0.2 h to yield
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the very high catalytic efficiency demonstrate the high utility of
this hydrogenation method for the production of the chiral
building block.
to Rh and phosphorus (3.1 and 4.8 Hz). The signals of both
carbon atoms of the double bond are strongly shifted to the
high-field region compared to the same signals in the free
substrate MAC and exhibit characteristic coupling to Rh and
phosphorus (Figure 4a). Both carbonyls in the 13C NMR
It has been reported that the asymmetric hydrogenation of
most ortho-substituted aryl enamides is hardly achieved in high
enantioselectivities compared with that of unhindered aryl
enamides.42,54 In 2006, Zhang and Zhang reported that
triphosphorus bidentate phosphine−phosphoramide ligands
exhibited excellent enantioselectivities even in the hydro-
genation of ortho-substituted aryl enamides.55 Furthermore,
they employed the ligands in the asymmetric hydrogenation of
1-naphthylenamide 34 to prepare 35, which is the key
intermediate to Cinacalcet hydrochloride (36), a drug used
for the treatment of hyperparathyroidism and hypercalcemia,
and achieved very high enantioselectivities up to 93.8% ee. We
applied our ligands to the same hydrogenation process to
evaluate their practical utility. As shown in Scheme 11, whereas
QuinoxP*-Rh did not exhibit very high selectivity (85% ee), the
rhodium complexes of more electron-rich BenzP* and
DioxyBenzP* furnished the product with remarkably high ee
values (95.1% ee and 97.1% ee). The observed enantioselectiv-
ities are superior to the previously reported ones, and in
conjunction with the catalytic efficiency and the mild reaction
conditions, we believe that this method is practically useful.
Mechanistic Study Using Rhodium Complex of
BenzP*. Interest in the details of the catalytic cycle and the
mechanism of enantioselection in the rhodium-catalyzed
asymmetric hydrogenation remains immense starting from
the discovery of the reaction itself.25,26 As the Rh-BenzP*
complex demonstrated excellent results in the rhodium-
catalyzed asymmetric hydrogenation, we decided to use it in
our mechanistic study, together with the most conventional
model substrate methyl α-acetamidocinnamate (MAC).
Hydrogenation of catalytic precursor [Rh((R,R)-BenzP*)-
(nbd)]SbF6 (37) with 1 atm of H2 at ambient temperature
smoothly gave solvate complex 38 after approximately 10 min
(Scheme 12). The addition of two equivalents of MAC to a
solution of 38 in deuteriomethanol at ambient temperature led to
immediate color change from pale yellow to dark red, indicating
the formation of a catalyst−substrate complex 39a (Scheme 12).
The structure of catalyst−substrate complex 39a was
elucidated from NMR data. The signal for CH proton of
the coordinated double bond resonates at δ 6.38 and is coupled
Figure 4. Section plots of 13C NMR spectra (100 MHz, CD3OD)
showing signals from carbon atoms of the coordinated double bond.
(a) Solution obtained by the addition of 2 eq of MAC to a
deuteriomethanol solution of 38 at 25 °C. Spectrum measured at
25 °C. (b) The same reagents were mixed at −100 °C and the sample
was put into the precooled probe of the NMR spectrometer. Spectrum
measured at −90 °C. (c) Computed spectra (BLYP/SDD(Rh)6-31G+
(2d,2p)/CPCM(methanol)).
spectrum are shifted to the low-field region and coupled to Rh.
These data unequivocally characterize 39a as chelated catalyst−
substrate complex.
Scheme 12. Generation of Solvate Complex and Formation of Catalyst−Substrate Complexes
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Figure 5. Section plots of phase-sensitive 2D NOESY spectra (400 MHz, CD3OD). (a) Solution obtained by the addition of 2 eq of MAC to a
deuteriomethanol solution of 38 at 25 °C. Spectrum measured at 25 °C. (b) The same reagents were mixed at −100 °C and the sample was put into
the precooled probe of the NMR spectrometer. Spectrum measured at −90 °C. The olefinic proton of 39a gives NOE only with the methyl group,
whereas in 39c, NOE between the olefinic proton and the tert-butyl group is observed. These data confirm the coordination modes in 39a and 39c.
Figure 6. Structures and relative free energies (25 °C) of catalyst-substrate complexes 39a−c optimized on the BLYP/SDD(Rh)6-31G+(2d,2p)/
CPCM(methanol) level of theory.
1
Furthermore, from the phase-sensitive 2D H−1H NOESY
spectrum of complex 39a taken at 298 K, it was possible to
determine the mode of coordination of the double bond in this
complex. The CH proton had only one NOE cross-peak in
the aliphatic region of the spectrum (Figure 5a), i.e., with the
methyl group of the adjacent phosphorus atom. As such NOE
is only possible in the case of re-coordination, this observation
enabled us to complete the structure elucidation of 39a. Other
NOEs observed in the spectrum confirmed this structural
assignment. (Details are described in the Supporting
Information.)
We tried to reproduce these results computationally by
optimizing of the structures of 39a and si-coordinated catalyst−
substrate complexes 39b and 39c on the BLYP/SDD(Rh)6-
31G+(2d,2p)/CPCM(methanol) level of theory (Figure 6).
The computed relative stabilities of 39a and 39c are in good
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Scheme 13. Computational Results for Four Different Hydrogenation Pathways Leading to (R)-Product
accord with the experimental data, as the equilibrium
concentration of 39b that is destabilized by 6.7 kcal/mol
would be negligible.
39c are very similar. The signal of the olefinic proton of 39c
resonates at δ6.55 and shows NOE with the signal of the tert-
butyl group, effectively confirming the si-coordination of the
double bond. On the other hand, the appearance of signals of
the coordinated double bond in the 13C NMR spectra of 39a
and 39b is markedly different (Figure 4). The chemical shifts of
CH and Ctert in 39a are almost the same; they exhibit
characteristic couplings with Rh and phosphorus. In the 13C
NMR spectrum of 39c, the signals of CH (δ = 85.7) and Ctert
(δ = 100.8) are far from each other and both are significantly
shifted to the low-field region compared to the corresponding
signals of 39a.
We conducted a computational screening for the possible
structures that would exhibit the characteristic 13C chemical
shifts of the coordinated double bond. As can be seen from
Figure 4, our computations reasonably well reproduce the
chemical shifts of the carbons of the coordinated double bond
in 39a and show convincingly that 39b is not the intermediate
observed at decreased temperatures. On the other hand, the
computed chemical shifts for catalyst-substrate complex 39c
(Figure 6, bottom) are in qualitative agreement with the
experimentally observed values. The coordination mode of the
double bond is changed from roughly orthogonal to the chelate
cycle in 39b to almost coplanar in 39c, which is 1.6 kcal/mol
more stable than 39b. A structure similar to 39c was previously
computed by Feldgus and Landis56 for the catalyst-substrate
complex of (R,R)-MeDuPHOS and α-acetamidocinnamonitrile,
but this is the first experimental observation of such species.
In order to gain a further insight into the mechanism of
enantioselection in the asymmetric hydrogenation catalyzed by
the BenzP*-Rh complex, we carried out two low-temperature
hydrogenation experiments.
It should be noted that although 39a is evidently more stable
than 39b, its “quadrant diagram” would show both methox-
ycarbonyl and phenyl substituents residing in the “hindered
quadrants” near the tert-butyl groups. This fact demonstrates
that qualitative speculations on the relative stabilities of the
intermediates based on the quadrant diagram approach are
often nonproductive. This has been already noticed by the
inventor of the quadrant diagram himself.12d As can be seen
from Figure 6, the methoxycarbonyl group of 39a effectively
escapes from the steric hindrance of the nearby tert-butyl group
via bending of the coordinated double bond, and the phenyl
group also escapes from the steric hindrance by taking a face-to-
tert-butyl conformation. The main factor contributing to the
relative instability of 39b is the necessity to form the substrate
chelate cycle with the oxygen atom of the amido carbonyl
group in close proximity to the tert-butyl substituent. Thus, the
corresponding Rh−O bond lengths are practically equal in the
optimized structures of 39a and 39b (2.15 Å). However, if the
closest distance between the NCO atom and the hydrogen
atom of the adjacent methyl group in 39a is 3.06 Å, one of the
hydrogen atoms of the tert-butyl group in 39b, is as close as
2.19 Å to the oxygen atom of the amido carbonyl. Hence, we
are certainly capable of distinguishing the relative hindrance
from a methyl group and a tert-butyl group, and correctly
assigning the “hindered quadrants”. However, without detailed
analysis of the structure, our conclusions on what these
quadrants actually “hinder” may be misleading.
To check if there are any kinetic products that might precede
the formation of 39a, we prepared a sample by adding MAC to
a solution of 38 at −90 °C and then set the sample in the
precooled probe of the NMR spectrometer. This led to the
detection of complex 39c. The 31P NMR spectra of 39a and
First, we attempted the low-temperature hydrogenation of
39a. Hydrogenation for 30 min at 2−3 atm H2 at −90 °C did
not result in the formation of any hydrogenation product.
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Figure 7. Profiles of the relative energies along four reaction pathways computed on the B3LYP/SDD(Rh)6-31G+(2d,2p)/CPCM(methanol) level
of theory with additional diffuse function for phosphorus. Relative free energies at 298 K are shown.
When the temperature was raised to −50 °C, hydrogenation
was completed after 30 min, and no intermediates were
detected. The hydrogenation product recovered from this
sample had 99.5% ee (R).
In the second experiment, an equilibrium mixture of 39c, 38,
and MAC was hydrogenated at −90 °C. In this case, the
hydrogenation of 39c was completed in 10 min at −90 °C,
whereas 39a formed during the hydrogenation. The ee of the
hydrogenation product was 99.7% (R).
These two experiments clearly show that 39a cannot be
directly hydrogenated; it must first dissociate its double bond to
form 39′, which is also in fast equilibrium with 39c.
Calculations show that the stabilities of 39b, 39c, and 39′
and the mixture of 38 and MAC are comparable. Hence, several
reaction pathways are conceivable in the catalytic cycle and
more detailed computations are necessary to confirm these
possibilities.
We have studied the oxidative addition of H2 to catalyst-
substrate complexes 39b, 39c, and 39′ and solvate complex 38
computationally (Scheme 13). Further reactions essential for
the completion of the catalytic cycle were also computed in
each case to compare the energetics of the corresponding
catalytic pathways. Computations were performed for the
unabridged molecules using the CPCM method (MeOH) for
modeling solvation effects.
distinguishable and merge in one low-energy pathway that leads
to the formation of the hydrogenation product upon
coordination of the double bond in 43 that yields dihydride
intermediate 44, which in turn undergoes migratory insertion
to give monohydride intermediate 45.
As there are no free coordination sites in chelating complex
39c, the dihydrogen molecule must coordinate above one of
the Rh−P bonds to form a molecular hydrogen complex that
serves as the initial species in the oxidative addition step. Landis
et al. looked into all four possible pathways for the oxidative
addition of dihydrogen to an analogue of 39c, the catalyst-
substrate complex of Rh-(R,R)-Me-DuPHOS and α-acetami-
docinnamonitrile.56−58 However, only two of those pathways
were found to have realistically low activation barriers. In the
case of 39c, the presence of the phenyl substituent at the
β-position of the prochiral substrate leaves only one possibility
for the formation of the molecular hydrogen complex (46), as
all other pathways are effectively blocked by the coordinated
substrate. Moreover, 46 is quite unstable: the reaction of 39c
with dihydrogen to yield 46 is endothermic by 20.5 kcal/mol.
Although the activation energy for the oxidative addition itself
is not high, the overall effective barrier for the formation of
dihydride intermediate 47 (rate limiting step: oxidative
addition) was computed to be 10.1 kcal/mol higher than that
for the formation of dihydride intermediate 44 (rate limiting
step: coordination of the double bond in 43). Thus, the
coordination of the double bond can hardly be expected to be
kept during the oxidative addition of hydrogen to 39c: most
probably, it would dissociate on the way to molecular hydrogen
complex 46, yielding much more stable (by 12.5 kcal/mol)
nonchelating molecular hydrogen complex 42.
The results are shown in Figure 7. The oxidative addition of
H2 to solvate complex 38 or nonchelating complex 39′ occurs
with very similar low activation barriers. These reactions
involve the coordination of the dihydrogen molecule at the
vacant coordination site, yielding molecular hydrogen com-
plexes 40 and 42, respectively. As 38 and 39′, 40 and 42, and
41 and 43 are easily interconvertible via the nonchelating
coordination of the substrate, these two pathways are hardly
The oxidative addition to the complex 39b was computed to
be still more demanding: the transition state for the oxidative
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Phosphorus Ligands in Asymmetric Catalysis; Wiley-VCH: Weinheim,
Germany, 2008; Vol. 1−3. (d) Grabulosa, A.; Granell, J.; Muller, G.
Coord. Chem. Rev. 2007, 251, 25. (e) Cui, X.; Burgess, K. Chem. Rev.
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(h) Ohkuma, T.; Kitamura, M.; Noyori, R. Catalytic Asymmetric
Synthesis; Ojima, I., Ed.; Wiley-VCH: Weinheim, Germany, 2000;
Chapter 1.
addition is 12.8 kcal/mol higher in energy than that for 39c.
Moreover, the structure of resulting dihydride intermediate 50
is strongly distorted and the double bond is only weakly bound
to Rh (Rh−C and Rh−CH distances are 3.81 and 3.85 Å,
respectively). As a result, we were unable to find a pathway for
the migratory insertion in that case.
Thus, the computational analysis suggests that the hydro-
genation takes place either via the dihydride pathway through
the solvate complex 38 or via nonchelating complex 39′,
because dihydrogen is readily coordinated to the vacant site of
these complexes. That means that the enantioselection must
take place at a later stage of the catalytic cycle, i.e., during the
recoordination of the double bond that leads to dihydride
intermediate 44.25,26 Intuitively, it is clear that the formation of
the chelate cycle should be more facile in the nonhindered
quadrant, that will result in a product with correct absolute
configuration. However, accurate computational analysis of
this step is difficult due to the involvement of solvent mole-
cules and the numerous possibilities for crossover of the re-
action pathways. We will describe these computations in future
publications.
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CONCLUSIONS
■
In summary, we have prepared three conformationally rigid
P-chiral phosphine ligands named QuinoxP*, BenzP*, and
DioxyBenzP*. Their rhodium complexes exhibited excellent
enantioselectivities of up to 99.9% and activities of up to 10000 h−1
TOF in the asymmetric hydrogenation of dehydroamino acid
derivatives and enamides. The practical utility of the asym-
metric hydrogenation using these ligands was demonstrated in
the efficient preparation of chiral ingredients of several im-
portant pharmaceuticals. In addition to the catalytic efficiency,
the ease of handling in air indicates the versatile utility of the
ligands in a wide range of transition-metal-catalyzed asymmetric
reactions.
The structurally simple and rigid ligand BenzP* was used for
the mechanistic study of rhodium-catalyzed asymmetric
hydrogenation. New aspects of the reaction pathways and the
enantioselection mechanism were revealed by NMR studies and
DFT calculations.
Butenschon, H. Chem. Commun. 2008, 5408. (f) Fox, M. E.; Jackson,
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Chem.Eur. J. 2010, 16, 871. (q) Zupancic, B.; Mohar, B.; Stephan,
M. Org. Lett. 2010, 12, 1296. (r) Zupancic, B.; Mohar, B.; Stephan, M.
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W.-L.; Li, S.; Zhou, Q.-L. J. Am. Chem. Soc. 2010, 132, 4538. (t) Shi,
S.-L.; Xu, L.-W.; Oisaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed descriptions of experimental procedures, X-ray
crystallographic data (CIF), spectral data of all new
compounds, HPLC and GC data for the determination of
enantiomeric excesses, data for NMR study, and summary of
for the calculation. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
imamoto@faculty.chiba-u.jp; gridnev.i.aa@m.titech.ac.jp
■
ACKNOWLEDGMENTS
The authors thank Professor Sylvain Juge,
Bourgogne, for valuable discussion.
■
́
the University of
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