A polymer-supported chiral dirhodium(II) complex: Highly durable and recyclable catalyst for asymmetric intramolecular C-H insertion reactions

Article abstract of DOI:10.1002/anie.201003730

A highly effective immobilization of [Rh2(S-PTTL)4] (PTTL=N-phthaloyl-tert- leucinate) has been achieved by copolymerization of monomer 1 with styrene and a flexible cross-linker. The immobilized catalyst promoted the title reaction at -78□°C with high en

Full text of DOI:10.1002/anie.201003730

Angewandte
Chemie
DOI: 10.1002/anie.201003730
Heterogeneous Catalysis
A Polymer-Supported Chiral Dirhodium(II) Complex: Highly Durable
À
and Recyclable Catalyst for Asymmetric Intramolecular C H Insertion
Reactions**
Koji Takeda, Tadashi Oohara, Masahiro Anada, Hisanori Nambu, and Shunichi Hashimoto*
Chiral dirhodium(II) complexes are highly effective catalysts
for a diverse array of asymmetric carbene transformations of
À
diazocarbonyl compounds, including cyclopropanation, C H
insertion, and rearrangement or cycloaddition via ylide
generation.[1] Although a number of systems have been
reported to provide enantioselectivities greater than
90% ee, the high cost of chiral dirhodium(II) complexes[2,3]
and the difficulty in catalyst recovery and recycling are major
limiting factors for their application in pharmaceutical
Figure 1. Chiral dirhodium(II) catalysts. MEPY=5-methoxycarbonyl-2-
oxopyrrolidinate, DOSP=N-(4-dodecylbenzenesulfonyl)prolinate,
PTTL=N-phthaloyl-tert-leucinate.
production.
The potential benefits of heterogeneous catalysts include
facilitation of catalyst separation from products and simpli-
fication of catalyst recycling. During the past few decades, a
great deal of attention has been paid to developing methods
for heterogenizing homogeneous chiral catalysts.[4] However,
there have been limited reports on polymer-supported
catalysts composed of several independent chiral ligands.[4,5]
A significant challenge in grafting chiral dirhodium(II)
complexes to supports is maintaining the chiral environment
around the parent homogeneous catalysts.[6,7] In this context,
Doyle et al. reported that immobilization of chiral dirhodiu-
m(II) carboxamidates such as [Rh2(5S-MEPY)4] (1; Figure 1),
could be achieved on NovaSyn Tentagel hydroxy resin and
Merrifield resin through an ester linkage to one of the
pyrrolidinone ligands; this immobilization led to effective and
reusable cyclopropanation catalysts with yields and selectiv-
ities comparable to those of the homogeneous catalysts.[8]
Davies et al. developed a novel approach for the immobiliza-
tion of chiral dirhodium(II) tetraprolinate catalysts such as
[Rh2(S-DOSP)4] (2), by using a highly cross-linked macro-
porous polystyrene (Argopore) resin with a benzyloxyme-
thylpyridine linker,[9] wherein the immobilization is consid-
ered to be a result of the cooperative effects of pyridine
coordination and microencapsulation. The noncovalent
immobilization strategy has not only realized the effective
use of the immobilized [Rh2(S-DOSP)4] complex as a
recyclable catalyst in asymmetric intermolecular cyclopropa-
À
nation and C H insertion reactions of donor/acceptor-sub-
stituted carbenoids, but has also demonstrated great versa-
tility for a diverse range of chiral dirhodium(II) catalysts.[9d]
Despite a great deal of work,[10–13] there still remains a need
for development in terms of catalyst activity, selectivity,
recyclability, and rhodium leaching. Herein, we report the
immobilization of [Rh2(S-PTTL)4] (3),[14–17] the most gener-
ally effective catalyst of our dirhodium(II) carboxylate
catalysts which incorporate N-phthaloyl-(S)-amino acids as
bridging ligands, and its use as a highly selective, durable, and
À
recyclable catalyst for asymmetric intramolecular C H inser-
tion reactions.
[*] Dr. K. Takeda, T. Oohara, Dr. M. Anada, Dr. H. Nambu,
Prof. Dr. S. Hashimoto
We envisaged the immobilization of 3 by the preparation
of dirhodium(II)-complex-containing monomer 4 and subse-
quent copolymerization (Scheme 1).[18,19] The design of poly-
mer-supported chiral dirhodium(II) complex 5 is character-
ized by the following features: 1) a chiral dirhodium(II)
complex is tethered to a polymer chain through one of the
ligands in the monomer 4 so there would be no adverse effects
on the chiral environment around the immobilized cata-
lyst,[19a] 2) immobilization using the monomer 4 should
produce polymer-supported complex 5 with no unreacted
linkers or free ligands,[20] 3) a long spacer between the
catalytic site and the polymer backbone would allow flexi-
bility of the catalyst system,[21] and 4) copolymerization could
lead to a uniform distribution of dirhodium(II) complex
within the polymer matrix to allow unimpeded access of a
substrate to the catalytic sites.[18,22]
Faculty of Pharmaceutical Sciences, Hokkaido University
Sapporo 060-0812 (Japan)
Fax: (+81)11-706-4981
E-mail: hsmt@pharm.hokudai.ac.jp
Homepage: http://www.pharm.hokudai.ac.jp/yakuzou/index-
e.html
[**] This research was supported, in part, by a Grant-in-Aid from
Innovation Plaza Hokkaido in the Japan Science and Technology
Agency and by a Grant-in-Aid for Scientific Research on Innovative
Areas (Project No. 2105: Organic Synthesis Based on Reaction
Integration) from the Ministry of Education, Culture, Sports,
Science and Technology (Japan). We thank S. Oka, M. Kiuchi, and T.
Hirose of the Center for Instrumental Analysis at Hokkaido
University for mass spectrometry measurements and elemental
analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201003730.
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Communications
revealed that the most favorable composition of
copolymer 5 was 994-45-101. A solution of monomers
and AIBN in chlorobenzene was dispersed in an
aqueous phase containing acacia gum and NaCl as
stabilizers, and the mixture was heated at 758C for
24 hours. The crude polymer was filtered off, washed
thoroughly with water, extracted with dichlorome-
thane and ethyl acetate in a Soxhlet apparatus, and
then dried under vacuum to provide 5 in 80% yield.
The resultant resin 5 having flexible cross-linkage
exhibited excellent swelling characteristics in sev-
eral organic solvents (see the Supporting Informa-
tion).[25] Elemental analysis indicated incorporation
of 0.27 mmol dirhodium(II) complex per gram of 5,
corresponding to the composition of the monomer
feed. The loading of rhodium on 5 was also
confirmed by inductively coupled plasma atomic emission
spectroscopy (ICP-AES) analysis. This observation suggests
that copolymerization of styrene (9) with 4-vinylbenzyloxy
groups in 4 and 10 produced a homogeneous composition of
the monomer ratio, and this may be because of similar
reactivity of the co-monomers.[26]
Scheme 1. Design of polymer-supported rhodium(II) complex 5.
The synthesis of mixed dirhodium(II) tetracarboxylates
with chiral ligands has not been previously reported. To the
best of our knowledge, there are only a few reports on the
synthesis of achiral [Rh2(R1COO)2(R2COO)2] species com-
posed of four independent ligands.[23] Consequently, construc-
tion of chiral [Rh2(R1COO)3(R2COO)] 4 became an objec-
The polymer-supported complex
5 was
examined for its catalytic performance in enan-
À
tioselective C H insertion of a-alkyl-a-diazo
ester 11 (Table 1).[15g] Rhodium(II) carbene
intermediates, generated from a-alkyl-a-diazo
À
esters bearing a C H bond adjacent to the
diazo carbon atom, tend to form a,b-unsatu-
rated esters via a 1,2-hydride shift.[27] Although
it is documented that low reaction temperatures
(À788C) are key to the suppression of b-
hydride elimination,[15g,16,28] there is no immo-
bilized dirhodium(II) catalyst available for
carbene transformations below room temper-
ature. The reaction of 11 with 2 mol% of the
immobilized catalyst 5 proceeded at À788C to
provide methyl cis-2-phenylcyclopentane-1-car-
boxylate (12) as the sole product in 94% ee, and
there was no trans isomer 13 or alkene product
14, even though catalyst 5 displayed low reac-
tivity relative to 3 (Table 1, entry 1 versus 2).[29]
Scheme 2. Preparation of the rhodium(II)-catalyst-containing monomer 4. DMF=N,N’-
dimethylformamide.
À
Table 1: Rhodium(II)-catalyzed enantioselective C H insertion of a-
diazo ester 11.
tive. Toward this goal, we selected N-4-hydroxyphthaloyl-(S)-
tert-leucine (6) as a replaceable ligand (Scheme 2). Treatment
of 3 with 6 in refluxing chlorobenzene gave an equilibrium
mixture of dirhodium(II) complex 7 and 3, which were readily
separable by column chromatography on silica gel. The
desired complex 7 was isolated in 40% yield; 3 was recovered
in 50% yield. A three-cycle sequence of ligand-exchange
reactions of recovered 3 and 6 furnished complex 7 in 74%
overall yield. O-alkylation of complex 7 with 6-(4-vinyl-
benzyloxy)bromohexane (8) afforded monomer 4 in 92%
yield.
Entry
RhII
Cycle no.
t [h]
Yield [%][a]
ee [%][b]
1[c]
2
3
4
5
3
5
5
5
5
–
1
5
10
20
0.5
4
4
4
4
85
85
84
83
81
95
94
95
95
94
The polymer-supported chiral dirhodium(II) catalyst 5
was prepared by suspension copolymerization[24] of 4 with
styrene (9) and 1,6-bis(4-vinylbenzyloxy)hexane (10) as a
[a] Yield of isolated product 12. [b] Determined by HPLC analysis.
[c] 1 mol% of [Rh2(S-PTTL)4] (3) was used. See Ref. [15g].
cross-linker (Scheme 3).
A survey of monomer ratios
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smoothly at À608C to afford cis-dihydroben-
zofuran 16 as the sole product and in a
similarly high yield and asymmetric induction
as those found with the homogeneous cata-
lyst 3 (Table 2, entry 1 versus 2). Further-
more, catalyst 5 was recyclable (15 times)
with no apparent loss of reactivity or enan-
tioselectivity (Table 2, entries 3–5). To deter-
mine the effect of the surface area upon the
reaction rate, the reaction with pulverized
polymer 5 was explored (Table 2, entry 6).
Interestingly, the surface area of catalyst 5
had little effect upon the reaction time for
full conversion. These results suggest that the
reaction with 5 proceeds not only on the
surface of the beads but also within the
polymer matrix. Therefore, it seems likely
that the swelling of polymer 5 in toluene
provides free diffusion of the reactant and
product to and from the catalytic sites.
Evidence for a uniform dispersion of
Scheme 3. Preparation of the polymer-supported chiral rhodium(II) complex 5.
AIBN=2,2’-azobisisobutyronitrile.
dirhodium(II) complex in the polymer
matrix was obtained from a cross-section
analysis of polymer 5 using a scanning
electron microscopy with an X-ray micro-
analyzer (SEM-XMA; see the Supporting Information).
Thus, the efficiency of catalyst 5 may be attributed to the
combination of good swelling properties and uniform dis-
persion of the dirhodium(II) complex within the polymer
matrix.[30]
This result indicates that the present method of immobiliza-
tion using monomer 4 produced very little effect on the chiral
environment around the immobilized catalyst. Since catalyst 5
displayed adequate activity and selectivity, attention was next
turned to the potency of its recovery and reuse (Table 1,
entries 3–5). After the reaction was complete, the liquid phase
containing the product was easily separated from the solid
catalyst 5 by cannulation. The robust catalyst 5 could be used
20 times, under the same reaction conditions used for the first
cycle, with virtually no drop in yield or enantioselectivity.
Another illustration of practical advantages of the immo-
bilized catalyst 5 was provided through asymmetric intra-
The utility of the immobilized catalyst 5 was additionally
tested by employing enantioselective intramolecular aromatic
C H insertion of a-diazo-b-ketoester 18 to form substituted
À
indanone 19, which is a key intermediate in asymmetric
À
Table 3: Rhodium(II)-catalyzed enantioselective C H insertion of a-
diazo-b-ketoester 18 using Argonaut quest-210.
À
molecular C H insertion of aryldiazoacetate 15 to afford a
dihydrobenzofuran neolignan system (Table 2).[9d,15f] The
reaction of 15 in the presence of 2 mol% of 5 proceeded
À
Table 2: Rhodium(II)-catalyzed enantioselective C H insertion of aryl-
diazoacetate 15.
Entry
RhII
Cycle no.
t [min]
Yield [%][a]
ee [%][b]
1
2
3
4
5
3
5
5
5
5
–
1
10
50
100
5
89
86
90
90
88
91
91
91
91
92
20
20
20
20
[a] Yield of isolated product 19. [b] Determined by HPLC analysis of the
product after demethoxycarbonylation.
Entry
RhII
Cycle no.
t [h]
Yield [%][a]
ee [%][b]
1[c]
2
3
4
3
5
5
5
5
5
–
1
5
10
15
–
0.5
2
2
2
2
87
83
84
84
80
83
90
91
91
91
90
91
synthesis of FR115427 (Table 3).[9d,15a] The reaction of 18 with
2 mol% of 5 at room temperature was conducted using an
Argonaut quest-210 parallel synthesizer[31] for easy catalyst
separation and catalyst recycling. The immobilized catalyst 5
exhibited essentially the same product yield and enantiose-
lectivity as those found with the homogeneous catalyst 3
5
6[d]
2
[a] Yield of isolated product 16. [b] Determined by HPLC analysis.
[c] 1 mol% of [Rh2(S-PTTL)4] (3) was used. See Ref. [15f]. [d] Pulverized
catalyst 5 was used.
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Communications
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In conclusion, we have accomplished the immobilization
of [Rh2(S-PTTL)4] (3) by copolymerization of dirhodium(II)-
complex-containing monomer 4 with styrene (9) and the
flexible cross-linker 10. To the best of our knowledge,
complex 4 is the first example of a chiral mixed dirhodium(II)
tetracarboxylate. Tethering a chiral dirhodium(II) complex to
a polymer chain through one of the ligands in 4 had no
deleterious effect on the chiral environment around the
immobilized catalyst. The immobilized catalyst 5 promoted
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À
asymmetric C H insertions even at À788C with high enan-
tioselectivity and could be used for up to 100 sequential
applications with a low leaching level, a feature of which
results from the combination of good swelling properties and
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Received: June 18, 2010
Published online: August 18, 2010
À
Keywords: asymmetric catalysis · C H activation ·
.
heterogeneous catalysis · immobilization · rhodium
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