Relay catalysis using a rhodium complex/chiral Bronsted acid binary system: Enantioselective reduction of a carbonyl ylide as the reactive intermediate

Article abstract of DOI:10.1002/anie.201107805

Pass the baton: A one-pot relay catalysis for a carbonyl ylide formation/enantioselective reduction sequence using a dirhodium(II) tetracarboxylate and chiral phosphoric acid catalyst system is described. The four-step transformation involves a rhodium ca

Full text of DOI:10.1002/anie.201107805

Angewandte
Chemie
DOI: 10.1002/anie.201107805
Asymmetric Catalysis
Relay Catalysis Using a Rhodium Complex/Chiral Brønsted Acid
Binary System: Enantioselective Reduction of a Carbonyl Ylide as the
Reactive Intermediate**
Masahiro Terada* and Yasunori Toda
Carbonyl ylides are generally non-isolable reactive inter-
mediates and have been extensively utilized as the dipole in
1,3-dipolar cycloaddition reactions with electron-deficient
and electron-rich dipolarophiles to afford polycyclic com-
pounds including five-membered oxacycles.[1] The most
efficient method for generating the carbonyl ylide is the
interaction of a metal carbene complex with the oxygen atom
of a carbonyl group. One practical way of generating metal
carbene complexes as a precursor of carbonyl ylides is the
decomposition of a-diazocarbonyl compounds by rhodium
catalysts,[1,2] and significant progress has been made in
developing stepwise sequences for rhodium carbene/carbonyl
ylide formation. However, this sequential process with
carbonyl ylides has been applied only to 1,3-dipolar cyclo-
addition reactions and, to the best of our knowledge, further
utilization of this attractive intermediate has never been
demonstrated in any range of organic transformations. To
broaden the scope of the synthetic applicability of the
carbonyl ylide, we envisioned the combination of an organo-
catalytic method with a rhodium-catalyst-initiated reaction
sequence in one pot.[3]
the binary catalytic system. One is that each reactant is
activated simultaneously by one type of catalyst; for instance,
a metal catalyst is used to activate the nucleophile while an
organocatalyst is used to activate the electrophile in a coop-
erative manner.[4] The other is the consecutive transformation
using a binary catalytic system, that is, relay catalysis for
a multistep sequence in which each catalyst promotes one
type of reaction in the sequence in one pot.[5] Herein, we
report an unprecedented relay catalysis[5] for a carbonyl ylide
formation/enantioselective reduction sequence using a binary
catalytic system[6] that consisting of the dirhodi-
um(II) tetracarboxylate 1 and chiral phosphoric acid 2 as
a chiral Brønsted acid catalyst[7,8] (Scheme 1). The proposed
relay catalysis involves a four-step transformation: a) decom-
position of the a-diazocarbonyl compound 3 by 1 to generate
Combined use of a transition-metal catalyst and an
organocatalyst has stimulated intensive interest in recent
years,[3] as it could potentially enable highly efficient and/or
unprecedented transformations in
a one-pot operation.
Indeed, excellent transformations have been established by
taking advantage of both of these catalytic approaches, where
two types of catalyst combinations have been developed in
[*] Prof. Dr. M. Terada, Y. Toda
Department of Chemistry, Graduate School of Science
Tohoku University, Aramaki, Aoba-ku, Sendai 980-8578 (Japan)
E-mail: mterada@m.tohoku.ac.jp
Homepage: http://www.orgreact.sakura.ne.jp/index.html
Prof. Dr. M. Terada
Research and Analytical Center for Giant Molecules
Graduate School of Science, Tohoku University
Aramaki, Aoba-ku, Sendai 980-8578 (Japan)
[**] This work was partially supported by the Japan Society for the
Promotion of Science (JSPS) through a Grant-in-Aid for Scientific
Research (Grant No. 23655077)), a Grant-in-Aid for Scientific
Research on Innovative Areas “Advanced Molecular Transforma-
tions by Organocatalysts” from the MEXT (Japan), and the Uehara
Memorial Foundation. We gratefully acknowledge Prof. Shunichi
Hashimoto (Hokkaido University) for providing the chiral dirho-
dium(II) tetracarboxylate complexes 1d and 1e. We also thank JSPS
for a research fellowship for Young Scientists (Y.T.).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201107805.
Scheme 1. Relay catalysis using a dirhodium(II) tetracarboxylate/chiral
phosphoric acid binary system for consecutive transformations.
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the rhodium carbene complex A; b) subsequent intramolec-
ular cyclization to afford the carbonyl ylide equivalent B (or
tautomerization to oxidopyrylium equivalent B’); c) proto-
nation of this transient species by 2 to afford ion pairs of the
stable isobenzopyrylium ion C and the conjugate base of 2;
and d) termination through a reduction of the cationic
intermediate C using the Hantzsch ester (4)[9] under the
influence of chiral conjugate base 2À to afford the isochro-
man-4-one derivative 5 in an optically active form.
At the outset of our studies, we conducted a control
experiment in the absence of the chiral catalyst 2. The
reaction was performed using the a-diazocarbonyl compound
3aa, 0.5 mol% of [Rh2(OAc)4] (1a), and 1.5 equivalents of
the Hantzsch ester (4) in CH2Cl2 at 308C for 5 hours (Table 1,
entry 1). The reaction proceeded cleanly to afford the racemic
high enantioselectivity, despite the fact that the reaction
proceeded without the chiral acid 2 under the same reaction
conditions (308C, 5 h; see entry 1 in Table 1).[12] Additional
optimization of the catalyst through changes in the substitu-
ent G and the backbone of the binaphthyl unit revealed that
slightly higher chemical yields and enantioselectivities were
obtained with the use of 2b bearing 9-phenanthryl substitu-
ents (Table 1, entry 3). Modification of the catalyst backbone,
thus the octahydrobinaphthyl 2c, however, resulted in
a decrease in the enantioselectivity (Table 1, entry 4). Screen-
ing of reaction temperature led to disappointing results; the
enantioselectivities were reduced when the temperature was
decreased to 108C or increased to 408C (Table 1, entries 5 and
6). Additional investigation of the effect of the ester
substituent in diazocarbonyl compound 3 demonstrated that
the introduction of sterically less demanding substituents
proved to be beneficial for enantioselectivity; the enantiose-
lectivity of methyl ester 6ca is as high as that of ethyl ester 6aa
(Table 1, entries 3, 7, and 8).
Table 1: Optimization of relay catalysis reaction conditions.[a]
In an effort to gain mechanistic insight into the present
binary catalytic system, we attempted the reaction using
several dirhodium(II) tetracarboxylates 1, including chiral
dirhodium(II) complexes 1c–e (Table 2). As shown in
Table 1, entry 1, the diazocarbonyl 3aa underwent the con-
secutive reaction to give 5aa without the chiral acid 2,
whereas the enantioenriched 5aa was obtained in the
presence of the chiral acid 2. One plausible pathway to
afford the enantioenriched 5aa is that a chiral dirhodium(II)
complex possessing chiral phosphate ligand(s) may serve as
an enantioselective catalyst.[13] Thus, ligand exchange would
partially occur between the acetate groups in [Rh2(OAc)4]
(1a) and 2 to generate a chiral dirhodium(II) complex. We
therefore employed [Rh2(esp)2] (1b) having tethered dicar-
boxylate ligands[14] to prevent the plausible ligand exchange
reaction. As shown in entry 1 in Table 2 and entry 3 in
Table 1, comparable enantioselectivities were observed
despite the fact that the extent of the ligand exchange
should be different between 1a and 1b.[15] These results imply
that dirhodium(II) complexes, even when chiral dirhodi-
um(II) complexes might be generated, do not participate in
the stereo-determining step, which is the transient assembly
Entry
2
3
6
Yield [%][b]
ee [%][c]
1
2
3
4
none
2a
2b
2c
2b
2b
2b
2b
3aa
3aa
3aa
3aa
3aa
3aa
3ba
3ca
6aa
6aa
6aa
6aa
6aa
6aa
6ba
6ca
91
88
90
85
81
82
85
83
–
89
90
80
84
88
60
90
5[d]
6[e]
7
8
[a] Unless otherwise noted, all reactions were carried out using 1a
(0.001 mmol, 0.5 mol%), (R)-2 (0.01 mmol, 5 mol%), 3 (0.2 mmol), and
4 (0.3 mmol) at 308C for 5 h. The solution of 3 in CH2Cl2 (1 mL) was
added to the solution of 1a, (R)-2, and 4 in CH2Cl2 (1 mL) by syringe
pump over a 1 h period. [b] Yield of isolated 6 (2 steps). [c] The
enantiomeric excess of 6 was determined by HPLC analysis using a chiral
stationary phase. The absolute configuration at the C1 of 5aa was
determined to be S by X-ray crystallographic analysis after derivatization
to the 4-bromobenzoyloxy isochromene derivative. See the Supporting
Information for details. [d] At 108C for 48 h. [e] At 408C for 4 h.
À
of the C H bond-forming step to generate the stereogenic
centers at C1 (and C3) of the isochromanone derivative 5aa.
To obtain direct evidence as to whether a dirhodium(II)
complex is involved in the stereo-determining step, we
investigated the consecutive transformation using the chiral
dirhodium(II) complexes 1c–e.[16,17] Although these three
chiral complexes have been reported as efficient enantiose-
lective catalysts in a range of organic transformations, these
complexes yielded the racemic products 5aa in the absence of
2 (Table 2, entries 2, 4, and 6). In sharp contrast, the combined
use of the chiral acid 2b with chiral dirhodium(II) complexes
resulted in the formation of the enantioenriched 5aa (Table 2,
entries 3, 5, and 7), with enantioselectivities as high as that
obtained by the original method using the achiral dirhodi-
um(II) 1a (see Table 1, entry 3). These results strongly
suggest that the present transformation sequence involves
a four-step process as proposed in Scheme 1 and, in the final
step, a rhodium-free intermediate, that is isobenzopyrylium C,
isochromanone derivative 5aa. The enol tautomer of 5aa was
then entrapped by a benzoyl group to afford the benzoyloxy
isochromene derivative 6aa as a racemic sample for chiral
stationary phase HPLC analysis. Although 3aa underwent the
transformation without 2, we investigated the proposed one-
pot relay catalysis in the presence of 5 mol% of the chiral acid
2a where G is a 9-anthryl group (Table 1, entry 2).[10,11]
Delightfully, the reaction sequence gave rise to 6aa with
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Table 2: Mechanistic investigation using (chiral) dirhodium(II) tetra-
Table 3: Scope of relay catalysis.[a]
carboxylate complexes.[a]
Entry
3
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
3ab: Ar=4-ClC6H4-, R1 =R2 =H
3ac: Ar=4-MeOC6H4-, R1 =R2 =H
3ad: Ar=4-MeC6H4-, R1 =R2 =H
3ae: Ar=3-MeC6H4-, R1 =R2 =H
3af: Ar=2-MeC6H4-, R1 =R2 =H
3ag: Ar=Ph, R1 =H, R2 =Br
93
84
90
89
92
85
81
86
87
89
90
88
92
74
3ah: Ar=Ph, R1 =Cl, R2 =Cl
[a] Unless otherwise noted, all reactions were carried out using 1a
(0.001 mmol, 0.5 mol%), (R)-2b (0.01 mmol, 5 mol%), of 3 (0.2 mmol),
and of 4 (0.3 mmol). The solution of 3 in CH2Cl2 (1 mL) was added to the
solution of 1a, (R)-2b, and 4 in CH2Cl2 (1 mL) by syringe pump over a 1 h
period. [b] Yield of isolated 6 (2 steps). [c] The enantiomeric excess of 6
was determined by HPLC analysis using a chiral stationary phase.
Entry
1
2b [mol%]
Yield [%][b]
ee [%][c]
however, the enantioselectivities were significantly depen-
dent upon the substituent pattern, with the highest enantio-
selectivity achieved when R1 = H.
1
2
3
4
5
6
7
1b
1c
1c
1d
1d
1e
1e
5
90
84
83
73
75
78
79
89
none
5
none
5
none
5
<1
90
<1
89
<1
90
In conclusion we have demonstrated a one-pot relay
catalysis for a carbonyl ylide formation/enantioselective
reduction sequence using a binary catalytic system consisting
of a dirhodium(II) tetracarboxylate and a chiral phosphoric
acid as a chiral Brønsted acid catalyst. The proposed relay
catalysis is composed of four consecutive reactions involving
isobenzopyrylium as a reactive key intermediate. More
importantly, the use of the chiral phosphoric acid was found
to be essential for obtaining the corresponding products in an
enantioselective fashion, which was confirmed by mechanistic
investigations using chiral dirhodium(II) complexes. By virtue
of the reactive isobenzopyrylium intermediate under the
influence of chiral conjugate base 2À, the present method
would be applicable to the reactions with nucleophilic
components other than the Hantzsch ester, thus yielding
isochromanone derivatives in an enantioenriched form. Addi-
tional studies to elucidate the reaction mechanism in detail
and determine the origin of the stereochemical outcome of
the present consecutive transformation are in progress, with
the aim of developing efficient enantioselective transforma-
tions on the basis of the present relay catalysis.
[a] Unless otherwise noted, all reactions were carried out using
1 (0.001 mmol, 0.5 mol%), (R)-2b (0.01 mmol, 5 mol%), 3aa
(0.2 mmol), and of 4 (0.3 mmol). The solution of 3aa in CH2Cl2 (1 mL)
was added to the solution of 1, [(R)-2b], and 4 in CH2Cl2 (1 mL) by
syringe pump over a 1 h period. [b] Yield of isolated 6aa (2 steps). [c] The
enantiomeric excess of 6aa was determined by HPLC analysis using
a chiral stationary phase.
undergoes enantioselective reduction under the influence of
the chiral conjugate base of 2. It should be emphasized that
the use of the chiral phosphoric acid is crucial for obtaining
the corresponding products in optically active form.
Having clarified the relay catalysis and the process
involving four consecutive transformations, we additionally
investigated the present binary catalytic system using a range
of a-diazocarbonyl compounds 3. Table 3 summarizes experi-
ments carried out to probe the scope of the present trans-
formation. Investigation of the effect of the substituent on the
Ar group showed that comparable enantioselectivities were
observed irrespective of the electronic character and position
of the substituent introduced on the phenyl ring (Table 3,
entries 1–5). The a-diazocarbonyl compounds 3 having sub-
stituents on the basal aromatic ring also underwent the
consecutive transformation to afford isochromene derivatives
6 in good yields (Table 3, entries 6 and 7). In these cases,
Experimental Section
[Rh2(OAc)4] (1a, 0.5 mol%, 0.44 mg, 0.001 mmol), (R)-2b (5 mol%,
7.01 mg, 0.01 mmol), and Hantzsch ester (4, 67.6 mg, 0.30 mmol) were
added to a dried test tube. The atmosphere was replaced with argon
and then the mixture was dissolved in CH2Cl2 (1 mL). 3aa (89%
purity, 72.4 mg, 0.20 mmol) in CH2Cl2 (1 mL) was added to the
solution at 308C over a 1 h period using a syringe pump. After
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completion of the addition, the mixture was stirred at 308C for
additional 4 h and then the reaction mixture was cooled to 08C. NEt3
(139 mL, 1.0 mmol), BzCl (46.4 mL, 0.40 mmol), and DMAP
(10 mol%, 2.44 mg, 0.02 mmol) were added to the reaction mixture
at 08C and then the mixture was stirred at RT for 12 h. The reaction
mixture was directly purified by flash column chromatography on
silica gel (CH2Cl2) to give 6aa in 90% yield as a white solid. The
enantiomeric excess was determined by chiral stationary phase HPLC
analysis.
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Received: November 6, 2011
Revised: December 3, 2011
Published online: January 19, 2012
Keywords: asymmetric catalysis · organocatalysis · reduction ·
.
rhodium · ylides
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to a marked reduction in reproducibility of the enantioselectiv-
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