Iridium-catalyzed enantioselective hydrogenation of unsaturated heterocyclic acids

Article abstract of DOI:10.1002/anie.201301341

Spiral binding: A highly enantioselective hydrogenation of unsaturated heterocyclic acids has been developed by using chiral iridium/spirophosphino oxazoline catalysts (see scheme; BAr_F^-=tetrakis[3,5- bis(trifluoromethyl)phenyl]borate, Boc=tert-butoxycarbonyl). This reaction provided an efficient method for the preparation of optically active heterocyclic acids with excellent enantioselectivities. Copyright

Full text of DOI:10.1002/anie.201301341

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DOI: 10.1002/anie.201301341
Synthetic Methods
Iridium-Catalyzed Enantioselective Hydrogenation of Unsaturated
Heterocyclic Acids**
Song Song, Shou-Fei Zhu, Liu-Yang Pu, and Qi-Lin Zhou*
Chiral heterocycles are ubiquitous structures in natural
products and bioactive compounds.[1] Chiral heterocyclic
acid (HCA) moieties (1) are of special importance because
they are present in various pharmaceuticals (Scheme 1).[2] For
example, the N-heterocyclic carboxylic acid (R)-tiagabine is
an g-aminobutyric acid reuptake inhibitor marketed for the
treatment of epilepsy.[2a] Two typical heterocyclic acids, b-
proline and (R)-nipecotic acid, are key structural elements in
synthetic peptides.[2b–c] O-Heterocyclic carboxylic acids are
key intermediates in the synthesis of many chiral drugs, such
as terazosin[2d] and nebivolol.[2e]
The transition-metal-catalyzed enantioselective hydroge-
nation of unsaturated heterocyclic carboxylic acids is a direct
approach to chiral heterocyclic acids. Although progress on
the asymmetric hydrogenation of acyclic unsaturated carbox-
ylic acids has been remarkable,[3] satisfactory methods for the
asymmetric hydrogenation of cyclic unsaturated carboxylic
acids are lacking. Hydrogenation of unsaturated N-hetero-
cyclic carboxylic acids over heterogeneous palladium cata-
lysts modified with cinchona alkaloids gives ee values of up to
60%,[4] and hydrogenation of unsaturated O-heterocycle-3-
carboxylic acids (2: X = O, n = 1) with homogeneous ruthe-
nium catalysts bearing chiral phosphorus ligands[5] and
heterogeneous palladium catalysts modified with cinchona
alkaloids have been reported to give moderate to good
enantioselectivities.[6] However, asymmetric hydrogenation of
unsaturated O-heterocycle-2-carboxylic acids (2, n = 0) has
never been achieved. The development of efficient chiral
catalysts for the enantioselective hydrogenation of various
unsaturated heterocyclic acids is highly desirable.[7] Herein,
we report the highly enantioselective hydrogenation of
unsaturated N-heterocyclic acids and O-heterocyclic acids
catalyzed by chiral spirophosphine oxazoline iridium com-
plexes (3). This reaction provided an efficient method for the
preparation of optically active HCAs with up to 99% ee
(Scheme 1).
We chose N-Boc-1,2,5,6-tetrahydropyridine-3-carboxylic
acid (2a) as a substrate to evaluate the activity of the catalysts
3. The hydrogenation reactions were performed in the
presence of 1 mol% of 3 under 6 atm of H2 at 608C with
0.5 equivalents of Cs2CO3 as an additive.[8] The catalyst (Sa,S)-
3a, which has phenyl groups on the phosphorus atom and
a benzyl group on the oxazoline ring, afforded 1a in 100%
conversion with 65% ee (Table 1, entry 1). The substituents
on the P-phenyl rings of the ligand strongly affected the
enantioselectivity of the reaction. The catalyst (Sa,S)-3c,
which bears bulky 3,5-di-tert-butylphenyl groups on the
phosphorus atom, increased the enantioselectivity to
96% ee (entry 3). When (Sa,R)-3c, a diastereoisomer of
(Sa,S)-3c, was used as the catalyst both the conversion and
the enantioselectivity decreased (entry 4), thus indicating that
the configurations of (Sa,S)-3c are well matched for high
enantioselectivity. We also studied the effect of the substitu-
ent on the oxazoline ring of the catalyst. The catalyst (Sa)-3d,
which has an unsubstituted oxazoline ring, gave the highest
enantioselectivity (entry 5), and the catalyst loading could be
reduced to 0.5 mol% without diminishing the conversion or
enantioselectivity (entry 8). The use of 0.5 equivalents of
NEt3, 0.5 equivalents of Na2CO3, or 0.1 equivalents of Cs2CO3
as an additive lowered both the conversion and the enantio-
selectivity (entries 9–11). In the absence of a basic additive,
Scheme 1. Asymmetric hydrogenation of unsaturated heterocyclic
acids using chiral iridium catalysts. BArFÀ =tetrakis[3,5-bis(trifluorome-
thyl)phenyl]borate.
[*] Dr. S. Song, Prof. S.-F. Zhu, L.-Y. Pu, Prof. Q.-L. Zhou
State Key Laboratory and Institute of Elemento-organic Chemistry
Nankai University, Tianjin 300071 (China)
E-mail: qlzhou@nankai.edu.cn
[**] We thank the National Natural Science Foundation of China, the
National Basic Research Program of China (973 Program, No.
2011CB808600), and the Ministry of Education of China (B06005)
for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201301341.
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Table 1: Optimization of the reaction conditions.[a]
Table 2: Asymmetric hydrogenation of unsaturated N-heterocyclic
acids.[a]
Entry
1
Substrate
S/C[b]
200
Product
Yield [%]
94
ee [%][c]
97 (R)
Entry
Catalyst
Additive
Conv. [%][b]
ee [%][c]
1
2
3
4
5
(Sa,S)-3a
(Sa,S)-3b
(Sa,S)-3c
(Sa,R)-3c
(Sa)-3d
(Sa,S)-3e
(Sa,S)-3 f
(Sa)-3d
(Sa)-3d
(Sa)-3d
(Sa)-3d
(Sa)-3d
0.5 equiv Cs2CO3
0.5 equiv Cs2CO3
0.5 equiv Cs2CO3
0.5 equiv Cs2CO3
0.5 equiv Cs2CO3
0.5 equiv Cs2CO3
0.5 equiv Cs2CO3
0.5 equiv Cs2CO3
0.5 equiv NEt3
0.5 equiv Na2CO3
0.1 equiv Cs2CO3
none
0.5 equiv Cs2CO3
0.5 equiv Cs2CO3
100
100
100
64
100
100
100
100
88
100
77
<5
51
65
82
96
91
97
93
91
97
93
93
90
–
2
3
50
94
97
90 (R)
6
7
8[d]
9[d]
10[d]
11[d]
12[d]
13[d,e]
14[d,f]
200
95
(Sa)-3d
(Sa)-3d
55
96
4
500
100
95
98
97
99
78
[a] Reaction conditions: 0.5 mmol 2a, [substrate]=0.25 molLÀ1, 608C,
substrate/catalyst=100:1, H2 (6 atm). [b] Determined by H NMR
spectroscopy. [c] Determined by SFC analysis, using a chiral column, of
the corresponding anilide. [d] Substrate/catalyst=200:1. [e] Under
50 atm H2. [f] Under 1 atm H2. Boc=tert-butoxycarbonyl.
1
5[d]
[a] The reaction conditions were the same as those in Table 1, entry 8.
Full conversions were obtained in all cases. [b] Substrate to catalyst ratio.
[c] Determined by HPLC or SFC analysis, using chiral columns, of the
corresponding anilide (see the Supporting Information). [d] Used (Sa,S)-
3c as catalyst, without additive.
the conversion was less than 5%. Increasing the H2 pressure
to 50 atm substantially decreased both the conversion and the
enantioselectivity (entry 13), and the reaction under 1 atm of
H2 pressure also gave low conversion (entry 14).
We then investigated the substrate scope of the reaction
under the optimal reaction conditions by hydrogenating
a variety of unsaturated N-heterocyclic acids. The hydro-
genation of the five-membered-ring substrate 2b catalyzed by
(Sa)-3d (2 mol%), produced N-Boc b-proline (1b) in 94%
yield with 90% ee (Table 2, entry 2). A seven-membered-ring
unsaturated N-heterocyclic acid (2c) could be hydrogenated
to the N-Boc-protected b-amino acid 1c in 97% yield with
95% ee (entry 3). With (Sa)-3d, the substrate 2d was hydro-
genated to the cyclic g-amino acid 1d in 95% yield with 97%
ee (entry 4). To our delight, the hydrogenation of 2e, which
has a tertiary amine group, proceeded smoothly without an
additive when we used 1 mol% (Sa,S)-3c, thus producing the
desired amino acid 1e in 98% yield with 99% ee (entry 5).
Encouraged by the successful hydrogenation of unsatu-
rated N-heterocyclic substrates, we investigated the use of the
iridium catalysts 3 for the asymmetric hydrogenation of
unsaturated O-heterocycle-2-carboxylic acids, a reaction that
had not previously been achieved. With the catalyst (Sa,S)-3c,
the hydrogenation of the unsaturated O-heterocycle-2-car-
boxylic acids 2 f–k proceeded smoothly in MeOH under 6 atm
of H2 at 608C, thus affording the corresponding saturated
acids 1 f–k in high yields (96–99%) and excellent enantiose-
lectivities (Table 3, entries 1–6). The chiral acid 1k, a key
intermediate in the synthesis of nebivolol,[2e,7i] was easily
prepared in 99% yield with 93% ee by the asymmetric
hydrogenation of 2k with 0.2 mol% of (Sa,S)-3c. The iridium
complexes 3 were also suitable catalysts for the hydrogena-
tion of the unsaturated O-heterocyclic acids 2l–o to the
corresponding chiral HCAs in high yields (94–97%) and high
enantioselectivities (88–97% ee, entries 7–11). The catalyst
loading could be reduced to 0.1 mol% without compromising
either the yield or the enantioselectivity in the hydrogenation
of 2n (entry 10).
To demonstrate the potential utility of this catalytic
asymmetric reaction, we synthesized (R)-nipecotic acid (1p)
and (R)-tiagabine (1q; Scheme 2). (R)-Nipecotic acid,
a
potent g-aminobutyric acid reuptake inhibitor,[9] is
a simple cyclic g-amino acid, but it is difficult to synthesize.
The only catalytic asymmetric preparation of chiral 1p
required more than 10 steps.[10] In addition to being available
Scheme 2. The syntheses of (R)-nipecotic acid and (R)-tiagabine.
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Table 3: Asymmetric hydrogenation of unsaturated O-heterocyclic acids.[a]
catalyzed asymmetric hydrogenation of unfunctionalized
olefins.[12] In this study, we found that when the methyl ester
of 2a was subjected to the standard hydrogenation conditions,
no reaction occurred. To probe the possibility of migration of
the double bond during the hydrogenation, we carried out an
isotopic labeling experiment (Scheme 3). Hydrogenation of
Entry Substrate
S/C Product
Yield ee [%][b]
[%]
1
2
3
4
5
6
100
100
200
200
200
500
96 97
97 98
97 92
98 93
98 93
99 93 (S)
Scheme 3. Isotopic labeling experiment.
2a with D2 (6 atm) in CD3OD gave 1a with deuterium atoms
attached to the carbon atoms where the double bond was
originally located, thus indicating that the double bond did
not migrate during the hydrogenation reaction.
In conclusion, we have realized the highly enantioselec-
tive hydrogenation of unsaturated heterocyclic acids cata-
lyzed by chiral spirophosphine oxazoline iridium complexes.
The reaction provides a direct catalytic approach to the
synthesis of chiral heterocyclic acids. The concise syntheses of
(R)-nipecotic acid and (R)-tiagabine demonstrates that this
catalytic asymmetric reaction has the potential for wide
application in organic synthesis.
7[c]
50
94 88 (R)
95 97 (R)
8[c]
100
9[c]
100
1000
95 97
94 97
10[c]
11[d]
50
97 89
Experimental Section
General hydrogenation procedure:
A hydrogenation tube was
[a] Reaction condition: 0.5 mmol scale, [substrate]=0.25 molLÀ1, (Sa,S)-3c
as catalyst, 0.5 equiv Cs2CO3 as additive, H2 (6 atm), 608C, 20 h. [b] Deter-
mined by HPLC or SFC using chiral columns (see the Supporting
Information). [c] Used (Sa)-3d as catalyst. [d] Used (Sa,S)-3 f as catalyst.
charged with a stir bar, unsaturated heterocyclic acid 2 (0.5 mmol),
catalyst (Sa,S)-3, and Cs2CO3 (41 mg, 0.25 mmol) in an argon-filled
glove box. MeOH (2 mL) was injected into the hydrogenation tube
with a syringe. The tube was placed in an autoclave and purged five
times with hydrogen gas. The autoclave was charged with H2 gas to
6 atm, and the reaction mixture was stirred at 608C for 12 h before the
release of the H2 pressure. The reaction solution was acidified with 3n
HCl (pH 1) and extracted with Et2O (3 ꢀ 10 mL). The combined
extracts were washed with a saturated solution of NaCl (15 mL), dried
over MgSO4, and evaporated in vacuo. The crude product was
purified by flash chromatography on a silica gel column to give a pure
chiral acid. The chiral acid (0.5 mmol) reacted with aniline (50 mL,
0.55 mmol) in the presence of DMAP (4 mg, 0.032 mmol) and DCC
(110 mg, 0.55 mmol) in THF (2 mL) for 2 h. The reaction mixture was
filtered through celite. The filtrate was diluted with Et2O (10 mL),
washed with 3n HCl (10 mL), and saturated NaHCO3 (10 mL), dried
with MgSO4, and concentrated in vacuo. After flash chromatography
on a silica gel column, the resulting amide was analyzed by super-
critical fluid chromatography (SFC) or HPLC to determine the
ee value.
from the hydrogenation product 1a, (R)-nipecotic acid also
can be synthesized by direct hydrogenation of the corre-
sponding unsaturated N-heterocyclic acid guvacine (2p).
Using the catalyst (Sa,S)-3c, we hydrogenated 2p under
neutral conditions to obtain (R)-nipecotic acid in 99% yield
with 96% ee. (R)-Tiagabine (1q) was synthesized in 90%
yield with 99% ee by (Sa,S)-3c-catalyzed hydrogenation of
the unsaturated N-heterocyclic acid 2q and subsequent
treatment with 3n hydrochloric acid. The carbon–carbon
double bond conjugated to the carboxy group was hydro-
genated smoothly, whereas the double bond conjugated to the
thiophene groups remained unchanged. This excellent che-
moselectivity further demonstrates the merit of these chiral
spiro iridium catalysts.
Received: February 15, 2013
Published online: April 22, 2013
In a previous study, we demonstrated that the carboxy
group is indispensable in the hydrogenation of acyclic
unsaturated carboxylic acids catalyzed by chiral iridium
complexes of spirophosphino oxazoline ligands.[11] The mech-
anism of that reaction differs from the mechanism of iridium-
Keywords: heterocycles · hydrogenation · iridium · P,N ligands ·
synthetic methods
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