Neutral iridium catalysts with chiral phosphine-carboxy ligands for asymmetric hydrogenation of unsaturated carboxylic acids

Article abstract of DOI:10.1039/c6sc03764j

We developed neutral iridium catalysts with chiral spiro phosphine-carboxy ligands (SpiroCAP) for asymmetric hydrogenation of unsaturated carboxylic acids. Different from the cationic Crabtree-type catalysts, the iridium catalysts with chiral spiro phosphine-carboxy ligands are neutral and do not require the use of a tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (BAr_F^?) counterion, which is necessary for stabilizing cationic Crabtree-type catalysts. Another advantage of the neutral iridium catalysts is that they have high stability and have a long lifetime in air. The new iridium catalysts with chiral spiro phosphine-carboxy ligands exhibit unprecedented high enantioselectivity (up to 99.4% ee) in the asymmetric hydrogenations of various unsaturated carboxylic acids, particularly for 3-alkyl-3-methylenepropionic acids, which are challenging substrates for other chiral catalysts.

Full text of DOI:10.1039/c6sc03764j

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DOI: 10.1039/C6SC03764J
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Neutral iridium catalysts with chiral phosphine-carboxy ligands
for asymmetric hydrogenation of unsaturated carboxylic acids
Shuang Yang,a Wen Che,a Hui-Ling Wu,a Shou-Fei Zhu,*a and Qi-Lin Zhou*ab
Received 00th January 20xx,
Accepted 00th January 20xx
We developed neutral iridium catalysts with chiral spiro phosphine-carboxy ligands (SpiroCAP) for asymmetric
hydrogenation of unsaturated carboxylic acids. Different from the cationic Crabtree-type catalysts, the iridium catalysts with
DOI: 10.1039/x0xx00000x
chiral spiro phosphine-carboxy ligands are neutral and do not require the use of
a
tetrakis[3,5-
www.rsc.org/
–
bis(trifluoromethyl)phenyl]borate (BArF ) counterion, which is necessary for stabilizing cationic Crabtree-type catalysts.
Another advantage of the neutral iridium catalysts is that they have high stability and have a long lifetime in air. The new
iridium catalysts with chiral spiro phosphine-carboxy ligands exhibit unprecedented high enantioselectivity (up to 99.4% ee)
in the asymmetric hydrogenations of various unsaturated carboxylic acids, particularly for 3-alkyl-3-methylene-propionic
acids, which are challenging substrates for other chiral catalysts.
challenging substrates. Herein, we report the preparation of
iridium complexes with chiral spiro phosphine-carboxy ligands
(2, Scheme 1) and the use of the complexes for the
Introduction
Transition-metal-catalyzed asymmetric hydrogenation is one of
the most useful reactions for the synthesis of optical
compounds because of its perfect atom economy and
operational simplicity.1 Chiral ligands are essential for this
reaction. In the past decades, a tremendous number of chiral
ligands have been developed for the asymmetric hydrogenation
of pro-chiral unsaturated compounds.2 However, there are few
chiral ligands in which oxygen is the coordinating atom. To date,
only two chiral phosphine-amide ligands with oxygen as the
coordinating atom have been reported; these ligands were used
for rhodium- and iridium-catalyzed asymmetric hydrogenation
reactions of cyclic enamides and trisubstituted olefins,
respectively, with moderate to high enantioselectivity.3
hydrogenation of unsaturated carboxylic acids. These neutral
iridium catalysts have several advantages: (1) they do not
require
the
use
of
a
tetrakis[3,5-
molecular
–
bis(trifluoromethyl)phenyl]borate (BArF , has
a
weight of 863) counterion, which is necessary for stabilizing
chiral cationic Crabtree-type catalysts (also called Pfaltz
catalysts);5 (2) they have high stability and have a long lifetime
in air; and (3) they exhibit unprecedented high
enantioselectivity (up to 99.4% ee) in the asymmetric
hydrogenation of various unsaturated carboxylic acids,
particularly for 3-alkyl-3-methylenepropionic acids, which are
challenging substrates.
Recently, we developed iridium catalysts with chiral spiro
phosphine-oxazoline ligands and chiral spiro aminophosphine
ligands, which show high enantioselectivity for the asymmetric
hydrogenation of unsaturated carboxylic acids.4 Mechanistic
studies revealed that the carboxy group of the substrate
anchors the molecule to the catalyst and triggers the
hydrogenation reaction. On the basis of these results, we
Results and discussion
Iridium complexes
83%) by refluxing a mixture of [Ir(COD)Cl]2, chiral spiro
phosphine-carboxy ligands
(SpiroCAP),6 and Na2CO3 in CH2Cl2
2 were readily prepared with high yields (71‒
1
for 1 h (Scheme 1). These neutral complexes were very stable;
they can be purified by silica gel column chromatography and
envisioned that iridium complexes with
a chiral spiro
phosphine-carboxy ligand might efficiently catalyze the
asymmetric hydrogenation of unsaturated carboxylic acids.
Carboxy groups can be introduced into chiral ligands to tune the
electronic and steric properties of catalysts and thus offer new
opportunities to achieve asymmetric hydrogenation of
a.State Key Laboratory and Institute of Elemento-Organic Chemistry, Nankai
University, Tianjin 300071, China
Scheme 1 Synthesis of iridium complexes of chiral spiro phosphine-carboxy
ligands. The crystal structure of (S)-2d (hydrogen atoms omitted for clarity).
Selected bond lengths (Å) and angles (°) for (S)-2d: Ir–O 2.085(4), Ir–P 2.3516(17);
O–Ir–P 90.30(15).
b.Collaborative Innovation Center of Chemical Science and Engineering (Tianjin),
Tianjin 300071, China
† Electronic Supplementary Information (ESI) available: For CIF data of (S)-2d
,
experimental procedures, and characterization data. See DOI: 10.1039/x0xx00000x
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stored in air for a few months. The structure of (S)-2d was giving
Journal Name
esters ViewinArticlegOonloinde
3-alkyl-3-methylpropionate
confirmed by X-ray diffraction analysis of a single crystal enantioselectivities (up to 94% ee). We stDuOdIi:e1d0.t1h03e9a/Csy6SmCm03e7t6r4iJc
(Scheme 1), which revealed that (S)-1d coordinates to the hydrogenation of 3-methyleneheptanoic acid (5a) with iridium
iridium atom as an anionic ligand.7
complexes 2 as catalysts (Table 1). When the reaction was
performed with (S)-2a in the presence of base Cs2CO3 under 3
atm of hydrogen in methanol at 45 °C, the desired product, 3-
methyheptanoic acid (6a), was obtained in 82% ee (entry 1).
Catalysts with less bulky P-aryl groups, such as 3,5-
dimethylphenyl (2b), 4-methoxylphenyl (2c), and phenyl (2d),
exhibited slightly higher enantioselectivities (entries 2–4). In
contrast, catalysts (S)-34c and (S)-44f with chiral spiro P,N ligands
gave much lower enantioselectivities (35% and 66% ee,
respectively; entries 5 and 6). Other bases (K2CO3, Na2CO3, and
NEt3) gave lower enantioselectivities (entries 7–9), and
omission of the base resulted in a poor conversion of the
substrate (entry 10). Performing the reaction at 65 °C slightly
increased the enantioselectivity (entry 11). The use of higher-
molecular-weight alcohols as solvents led to higher
enantioselectivities (entries 12‒15), and nBuOH and tBuOH
proved to be the most suitable solvents, giving the desired
product in 93% ee. When the carboxy group of the ligand 1a was
replaced by a methyl ester, only racemic product was obtained
under identical reaction conditions, which clearly demonstrates
that the coordination of carboxyl group of ligand to the metal
of catalyst is necessary for enantiocontrol of reaction.
Table 1 Iridium-catalyzed asymmetric hydrogenation of 3-methyleneheptanoic acid[a]
entry catalyst
base
solvent time (h) conv. (%)b ee (%)c
1
2
3
(S)-2a
(S)-2b
(S)-2c
Cs2CO3
Cs2CO3
Cs2CO3
MeOH
MeOH
MeOH
0.5
0.5
0.5
100
100
100
82
83
83
4
5
(S)-2d
(S)-3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
MeOH
MeOH
MeOH
MeOH
0.5
2
100
100
100
100
100
100
27
84
35
66
78
55
76
70
Table 2 Asymmetric hydrogenation of 3-alkyl-3-methylenepropionic acids catalyzed by
(S)-2da
6
(S)-4
0.5
0.5
0.5
0.5
24
7
(S)-2d
(S)-2d
(S)-2d
(S)-2d
8
Na2CO3 MeOH
9d
10
NEt3
MeOH
MeOH
none
11e
12e
13e
14e
15e
(S)-2d
(S)-2d
(S)-2d
(S)-2d
(S)-2d
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
MeOH
nPrOH
iPrOH
0.5
0.5
0.5
0.5
0.5
100
100
100
100
100
88
90
91
93
93
nBuOH
tBuOH
a
Reaction conditions: 5a/catalyst/base = 0.5:0.005:0.25 (mmol), 2 mL solvent,
45 °C. Determined by 1H NMR. Determined by HPLC using a Chiralpak AD-H
column. d 1.0 equiv of base was used. e Performed at 65 °C.
b
c
Asymmetric hydrogenation of 3-alkyl-3-methylene-
carboxylic acids
5 is a useful reaction because the products,
a Reaction conditions and analytical methods were the same as those described in
entry 14 of Table 1. Full conversion was obtained in all cases.
chiral 3-alkyl-3-methylpropionic acids, are building blocks for
biologically active compounds.8 However, there are no well-
established methods for the asymmetric hydrogenation of 3-
alkyl-3-methylene-carboxylic acids. Uchida et al.9 and Zhang et
al.10 investigated this reaction by using Ru/BINAP and
Rh/DuanPhos as catalysts, respectively, but achieved only
moderate enantioselectivity (up to 74% ee). Alternatively, Pfaltz
Under the optimal reaction conditions (Table 1, entry 14),
various 3-alkyl-3-methylenepropionic acids
(5a
–j
)
were
hydrogenated in the presence of 1 mol % catalyst (S)-2d (Table
2). All the tested substrates underwent hydrogenation within
0.5 h to afford the desired chiral 3-methyl-carboxylic acids with
et al.11 reported a hydorgenation of
,-unsaturated esters
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reaction of commercially available 4-methyleneoxetan-2-one
good to excellent enantioselectivity (86–98% ee). The steric
bulk of the R group of the substrate had a remarkable influence
on the enantioselectivity; bulky alkyl groups favored high
enantioselectivity (6d–6g). The hydrogenation of 5j, which has
two C=C bonds, occurred only at the β-olefin; the remote olefin
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with a Grignard reagent, was hydrogenated in the presence of
DOI: 10.1039/C6SC03764J
0.1 mol % catalyst (R)-2d to produce acid (S)-6a in 99% yield
with 93% ee. Acid (S)-6a was reduced with LiAlH4 to alcohol
9 in
94% yield. Finally, was converted to (S)-14-methyloctadec-1-
9
ene by tosylation and subsequent coupling with a Grignard
reagent in 67% yield for the two steps. Thus, the total synthesis
of (S)-14-methyloctadec-1-ene was accomplished in 50% overall
yield starting from commercially available materials.
moiety was untouched.
A
deuterium-labeling experiment was performed to
determine whether the olefin migrated during the
hydrogenation reaction (Scheme 2). The absence of deuterium
at the α-position of hydrogenation product d-6a clearly showed
that the double bond did not migrate during the reaction.
Scheme 2 Deuterium-labeling experiment
In addition to 3-alkyl-3-methylenepropionic acids, other
representative unsaturated carboxylic acids, such as α-methyl
cinnamic acid (7a), tiglic acid (7b), α-phenyl butenoic acid (7c),
α-benzyloxy cinnamic acid (7d), 2-(4-isobutylphenyl)acrylic acid
Scheme 3 Total synthesis of (S)-14-methyloctadec-1-ene
(7e), and 2-methyleneheptanoic acid (7f), also underwent
hydrogenation catalyzed by (S)-2d (Table 3), producing the
corresponding chiral carboxylic acids in high yields (97–99%)
with excellent enantioselectivities (94–99.4% ee). These results
Conclusions
show that neutral iridium catalysts
2 are among the most
In summary, we developed a new type of chiral spiro
phosphine-carboxy ligand, which can form iridium complexes
without the need for a stabilizing counterion. Neutral iridium
complexes of these ligands catalyzed the asymmetric
hydrogenation of various unsaturated carboxylic acids with
excellent enantioselectivity. In particular, these catalysts
allowed us to achieve highly enantioselective hydrogenation of
3-alkyl-3-methylenepropionic acids, which are challenging
substrates for previously reported chiral catalysts. Additional
studies on the applications of these neutral iridium catalysts
with chiral phosphine-carboxy ligands to other asymmetric
reactions are underway in our laboratory.
efficient chiral catalysts reported to date for the asymmetric
hydrogenation of unsaturated carboxylic acids.4a,9-12
Table 3 Hydrogenation of other types of unsaturated carboxylic acidsa
Acknowledgements
We thank the National Natural Science Foundation of China, the
National Basic Research Program of China (2012CB821600), the
“111” project (B06005) of the Ministry of Education of China,
and the National Program for Support of Top-notch Young
Professionals for financial support.
a Reaction conditions and analytical methods were the same as those described in
entry 14 of Table 1. Full conversion was obtained in all cases.
The (S)-14-methyloctadec-1-ene is a female sex pheromone
of the peach leafminer moth (Lyonetia clerkella). Several
syntheses of (S)-14-methyloctadec-1-ene have been reported
using enzymatic catalysis,13 chiral starting materials,14 or chiral
auxiliaries.15 To demonstrate the potential application of the
asymmetric hydrogenation of 3-alkyl-3-methylenepropionic
acids in organic synthesis, we carried out a synthesis of (S)-14-
methyloctadec-1-ene (Scheme 3). 3-Methyleneheptanoic acid
5a, which was easily prepared in 80% yield by a ring-opening
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