Rh-catalyzed highly enantioselective synthesis of 3-arylbutanoic acids

Article abstract of DOI:10.1002/anie.200604810

(Chemical Equation Presented) It's in the mix: The reaction conditions - catalyst, additive, and solvent - have been optimized for the asymmetric hydrogenation of 3-aryl-3-butenoic acids. The rigid, chiral bisphospholane ligand (S_P,R_C)-DuanPhos is crucial to achieving high enantioselectivity.

Full text of DOI:10.1002/anie.200604810

Angewandte
Chemie
DOI: 10.1002/anie.200604810
Asymmetric Hydrogenation
Rh-Catalyzed Highly Enantioselective Synthesis of 3-Arylbutanoic
Acids**
Xianfeng Sun, Le Zhou, Chun-Jiang Wang, and Xumu Zhang*
Enantiomerically pure 3-arylbutanoic acids and their deriv-
atives such as chiral 3-arylbutanols are important intermedi-
ates for the synthesis of aromatic sesquiterpenes of the
bisabolane family[1] and useful building blocks in organic
synthesis.[2,3a] Avariety of asymmetric syntheses of the
carboxylic acids have therefore been developed, such as 1,4-
addition of organometallic reagents to chiral a,b-unsaturated
esters and amides,[3] diastereoface-differentiating alkylation
with a number of nucleophiles and chiral catalysts or
promoters,[4] and the Mitsunobu reaction of chiral secondary
benzylic alcohols.[5] However, low yields, moderate regiose-
lectivities, and narrow substrate scopes limit the potential
applications of these reactions. We envision that one of the
most effective methods for the construction of these moieties
will be asymmetric hydrogenation of the corresponding
prostereogenic 3-aryl-3-butenoic acids. Although significant
progress has been made in asymmetric hydrogenation of a-
arylacrylic acids and other a,b-unsaturated acids with various
ruthenium or rhodium complexes,[6] the asymmetric hydro-
genation of b,g-unsaturated carboxylic acids still remains a
major challenge owing to moderate enantioselectivities (24–
85% ee) and high catalyst loadings (1–2 mol%).[7] Herein we
report a Rh-catalyzed highly enantioselective hydrogenation
for the preparation of chiral 3-arylbutanoic acids which has
several outstanding features: 1) Selectivities of up to 99% ee
and turnover numbers (TONs) of up to 5000 can be achieved.
2) The combination of a highly rigid electron-donating P-
chiral bisphospholane ligand with optimal solvent and
additive effects is the key to efficient transformations.
3) The simplicity of obtaining substrates and highly enantio-
selective hydrogenation under mild conditions make this
approach very attractive and practical.
Afamily of prostereogenic unsaturated carboxylic acids
was prepared through a simple and versatile synthetic method
developed by Itoh et al.[8] using [Pd(PPh3)4] as a catalyst.[7b] As
claimed in Itohꢀs report, two advantages make the prepara-
tion of substrates especially suitable for large-scale synthesis.
First, reactions can be accomplished in one pot by a
palladium(0)-catalyzed coupling reaction of diketene with
an arylzinc chloride reagent, providing desired 3-aryl-3-
butenoic acids in high yields. Second, pure products can be
obtained easily by recrystallization or fractional distilla-
tion.[8,9]
Acrucial point to achieving high enantioselectivities and
activities for the asymmetric hydrogenation is finding effec-
tive catalysts.[10] We initiated our studies on the asymmetric
hydrogenation of 3-phenyl-3-butenoic acid by briefly screen-
ing several chiral phosphorus ligands (Figure 1). Although the
complexes [Rh(S,S,R,R)-TangPhos(cod)]BF4 (3a; cod =
[*] X. Sun, Prof. L. Zhou, Prof. X. Zhang
Department of Chemistry
The Pennsylvania State University
104 Chemistry Building, University Park, PA 16802 (USA)
Fax: (+1)814-863-8403
Figure 1. Structures of ligands for asymmetric hydrogenation.
E-mail: xumu@chem.psu.edu
Prof. L. Zhou
College of Science
Northwest A&F University
Yangling, Shaanxi, 712100 (P.R. China)
cyclooctadiene)[11]
and
[Rh(R,R)-Et-DuPhos(cod)]BF4
(3b)[12] were successful for the highly enantioselective hydro-
genation of various substituted olefins, only low enantiose-
lectivities were obtained at room temperature under low
hydrogen pressure (Table 1, entries 1 and 2). Hydrogenation
with [Rh(S)-Binapine(cod)]BF4 (3c)[13] (Table 1, entry 3)
resulted in 26% ee under analogous conditions, while the
Prof. C.-J. Wang
Green Catalysis Institute
Wuhan University
Hubei, 430072 (P.R. China)
[**] This work was supported by the US National Institutes of Health
(GM58832).
[14]
reaction with [Rh(S)-C3-TunePhos(cod)]BF4 offered poor
enantioselectivity (Table 1, entry 4). To our delight, up to
80% ee and 100% conversion were achieved with the highly
rigid electron-donating P-chiral bisphospholane complex
Supporting information for this article (including experimental
procedures and compound characterization data) is available on
the WWW under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2007, 46, 2623 –2626
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Communications
Table 1: Asymmetric hydrogenation of 3-phenyl-3-butenoic acid.[a]
is more strongly chelated to the transition-metal center than
the acid itself, resulting in higher enantioselectivity.[7b] Inter-
estingly, when 5 mol% of Et3N was added to the reaction
mixture, the solvent effect was diminished dramatically. All
reactions in different solvents provided comparable enantio-
selectivities (82–89% ee, Table 1, entries 10–15). In addition,
the polarity of the solvent was further examined by using
aqueous methanol as the solvent. The polarity of the mixed
solvent was found to be significant for achieving high
enantiomeric excess (Table 1, entries 16 and 17). The best
result, 97% ee, was achieved when MeOH/H2O (1:1, v/v) was
employed (Table 1, entry 17). It could be rationalized that the
Entry
Cat.[b]
Solvent
Et3N [mol%]
ee [%][c]
Config.[d]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
3a
3b
3c
3d
3e
3e
3e
3e
3e
3e
3e
3e
3e
3e
3e
3e
MeOH
MeOH
MeOH
MeOH
MeOH
iPrOH
CH2Cl2
toluene
THF
MeOH
EtOH
iPrOH
CH2Cl2
EtOAc
THF
0
0
0
0
0
0
0
0
0
5
5
5
5
5
5
5
30
7
S (+)
(+)
(+)
(+)
(+)
(+)
(+)
(+)
(+)
(+)
(+)
(+)
(+)
(+)
(+)
(+)
26
17
80
70
50
56
14
89
87
87
86
82
85
92
+
generation of the cationic rhodium(I) species, as a RhL2
fragment, was facilitated to coordinate with substrates in
polar solvents, which could play an important role in
determining the critical step for highly enantioselective
hydrogenation of 1a. The enhancement of ee might also be
attributed to the stabilization of the olefinic carboxylate anion
in polar solvents. However, much lower enantioselectivity and
reactivity were observed in 25% aqueous methanol owing to
the poor solubility of the substrate in the solvent (Table 1,
entry 18).
MeOH/H2O
(3:1)
17
18
3e
3e
MeOH/H2O
(1:1)
MeOH/H2O
(1:3)
5
5
97
(+)
To demonstrate the flexibility of this methodology, the
hydrogenation of a series of b,g-unsaturated carboxylic acids
was studied with Rh complex 3e under the optimized
conditions (Table 1, entry 17). As shown for 3-aryl-3-butenoic
acids (Table 2, entries 1–13), the hydrogenations proceeded
to completion and afforded the corresponding 3-arylbutanoic
acids in high yields (90–97%) with excellent enantioselectiv-
ities (94–99% ee). Outstanding selectivities of over 99% ee
were achieved in the hydrogenation of 3-(3-fluorophenyl)-
and 3-(4-chlorophenyl)-3-butenoic acids (Table 2, entries 7
and 9). These results indicated that the reaction system has a
high tolerance to the pattern and electronic properties of the
substituent on the phenyl ring of substrates. It is worth noting
that the Rh-DuanPhos-catalyzed hydrogenations of aliphatic
acids 1n and 1o were also conducted smoothly with good
enantioselectivities (74% and 70% ee, respectively) to pro-
duce 3-methyl-4-phenylbutanoic acid (2n) and 3-methylhep-
tanoic acid (2o), respectively, which are important intermedi-
ates in the synthesis of immunoregulatory agents (or their
precursors).[17] To the best of our knowledge, these results
represent the highest enantioselectivities in direct asymmetric
hydrogenation for the preparation of optically active 3-
arylbutanoic acids using chiral rhodium catalyst systems.
To address the potential of Rh-DuanPhos-catalyzed
asymmetric hydrogenation as a practical means for the
enantioselective synthesis of 3-arylbutanoic acids, substrate
3-(2-naphthyl)-3-butenoic acid (1m) was examined with a low
catalyst loading. Impressively, complex 3e displayed suffi-
cient catalytic activity under mild conditions. Under an initial
hydrogen pressure of 3 atm and at room temperature (sub-
strate/catalyst (S/C) = 5000, 5 mol% Et3N), 1m was hydro-
genated with full conversion within 24 h, resulting in 3-(2-
naphthyl)butanoic acid without any loss of optical purity.
In conclusion, high enantiomeric excesses were obtained
in the asymmetric hydrogenation of various b,g-unsaturated
carboxylic acids catalyzed with a Rh complex containing a
highly rigid electron-donating P-chiral bisphospholane ligand,
nd[e]
nd
[a] Reactions were carried out with 0.2 mmol of substrate in 2 mL of
solvent in the presence of 1 mol% of Rh catalyst for 12 h under an initial
hydrogen pressure of 3 atm. In all cases 1H NMR spectroscopy indicated
complete
conversion.
[b] 3a:
[Rh(S,S,R,R)-TangPhos(cod)]BF4;
3b: [Rh(R,R)-Et-DuPhos(cod)]BF4; 3c: [Rh(S)-Binapine(cod)]BF4;
3d: [Rh(S)-C3-TunePhos(cod)]BF4; 3e: [Rh(Sp,Rc)-DuanPhos(nbd)]SbF6.
[c] Determined by chiral GC. [d] Absolute configuration was determined
by comparison of the sign of the optical rotation with the reported data.
[e] Not determined because of low reactivity.
[Rh(Sp,Rc)-DuanPhos(nbd)]SbF6 (3e; nbd = 2,5-norborna-
diene)[15] (Table 1, entry 5).
Subsequently, the effect of solvents was investigated in an
effort to attain higher enantioselectivities. Strong solvent
dependency was observed in the reaction. As shown in
Table 1, complex 3e performed well in alcohols to give good
to high enantioselectivities (Table 1, entries 5 and 6), while
reaction in aprotic solvents such as dichloromethane, THF,
and toluene led to lower enantiomeric excesses (Table 1,
entries 7–9).
It has been reported that catalytic additives play a crucial
role in improving the reactivity and enantioselectivity in the
asymmetric hydrogenation of certain ketones, imines, and
simple olefins.[16] Moreover, it was discovered that asymmet-
ric hydrogenation of acids with the Rh–Diop catalyst system
could be improved remarkably by the addition of tertiary
amines.[7b] Accordingly, we tested a number of additives in our
reaction, such as nBu3N, iPr2EtN, phthalimide, and benzyl-
amine. The addition of Et3N had a striking effect on the
asymmetric induction (Table 1, entries 10–15), which was
consistent with Yamamotoꢀs report.[7b] Up to 89% ee was
obtained when 5 mol% of Et3N was present. Areasonable
explanation raised by Yamamoto et al. is that the olefinic
carboxylate anion formed with the addition of tertiary amine
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Chemie
Table 2: Rh-catalyzed asymmetric hydrogenation of b,g-unsaturated carboxylic acids 1.[a]
Entry
1
R
Product
Yield [%][b]
ee [%][c]
Config.[d]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
phenyl
2a
2b
2c
2d
2e
2 f
2g
2h
2i
2j
2k
2l
2m
2n
2o
93
91
93
94
95
92
93
90
93
91
94
93
97
92
85
97
98
96
97
97
94
>99
95
>99
98
98
S (+)
(À)
2-Me-C6H4
3-Me-C6H4
4-Me-C6H4
3-OMe-C6H4
4-OMe-C6H4
3-F-C6H4
(+)
(+)
(+)
S (+)
(+)
(+)
(+)
(+)
(+)
R (À)
S (+)
R (+)
R (+)
4-F-C6H4
4-Cl-C6H4
4-Br-C6H4
4-CF3-C6H4
1-naphthyl
2-naphthyl
benzyl
98
97
74
70
n-butyl
[a] Reactions were carried out with 0.1 mol% of Rh-DuanPhos complex and 5 mol% Et3N for 12 h under an initial hydrogen pressure of 3 atm in
MeOH/H2O (1:1). In all cases 1H NMR spectroscopy indicated complete conversion. [b] Yield of isolated product. [c] The enantiomeric excesses were
determined by chiral HPLC or chiral GC (see the Supporting Information). [d] The absolute configurations of 2a, 2 f, 2l, 2m, 2n, and 2o were assigned
by comparison of the observed optical rotation with reported data.
by chiral GC (Gamma Dex 225 and Beta Dex 325) or HPLC (Chiral
OD and OJ-H).
DuanPhos. High turnover numbers for selected substrates
were also achieved under mild conditions. This strategy
establishes one of the most practical methods for the synthesis
of enantiomerically pure 3-arylbutanoic acids and their
derivatives, which are important pharmaceutical intermedi-
ates and chiral building blocks in organic synthesis. Further
investigation of the substrate scope with this catalytic system
will be reported in due course.
Received: November 27, 2006
Published online: March 6, 2007
Keywords: asymmetric catalysis · carboxylic acids ·
.
enantioselectivity · hydrogenation · rhodium
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Experimental Section
General procedure: Asuspension of ( Sp,Rc)-DuanPhos (140 mg,
0.366 mmol) in THF (6 mL) was added to a solution of [Rh-
(nbd)2]SbF6 (182.6 mg, 0.35 mmol) in THF (2 mL) at À208C. The
resulting red solution was allowed to warm to room temperature and
stirred for an additional 15 min. The solution was concentrated to
about 6 mL. Then Et2O (25 mL) was added under vigorous stirring,
during which an orange precipitate was formed. The precipitate was
filtered off and washed with Et2O (2 ” 10 mL) to afford the orange
solid complex (198 mg, 67%).[15] The complex was stored in a
nitrogen-filled glovebox for further usage. The complex (16.3 mg,
0.02 mmol) was dissolved in degassed methanol (100 mL) in a
glovebox. A10-mL portion of the complex solution was divided
equally among 10 vials. Et3N (1.01 mg, 0.01 mmol) in 1 mL of
degassed water was added to each of the vials, followed by b,g-
unsaturated acid substrate (0.2 mmol, S/C = 1000). The resulting
solution was then transferred into an autoclave and charged with
3 atm of hydrogen. The hydrogenation was performed at room
temperature for 12 h. The hydrogen was released carefully, and the
solvent was removed by evaporation. The residue was dissolved in
diethyl ether (20 mL) and extracted with 3 equivalents of aq. NaOH
(2 ” 30 mL). The alkaline solution was acidified with 6 equivalents of
aq. HCl, and then extracted with diethyl ether (3 ” 20 mL). The ether
extracts were washed with brine, dried over anhydrous Na2SO4, and
concentrated by evaporation. The residue was subject to silica gel
column chromatography using hexanes/ether (8:1) as eluent for
further purification. Enantiomeric excesses were directly measured
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