Linked-BINOL: An Approach towards Practical Asymmetric Multifunctional Catalysis

Article abstract of DOI:10.1002/1615-4169(200201)344:1<3::AID-ADSC3>3.0.CO;2-2

The development and application of a novel linked-1,1′-binaphthol (linked-BINOL) as an approach towards practical asymmetric multifunctional catalysis is described. Linked-BINOL was first designed to increase the stability of a Ga-Li-BINOL complex against

Full text of DOI:10.1002/1615-4169(200201)344:1<3::AID-ADSC3>3.0.CO;2-2

REVIEWS
Linked-BINOL: An Approach towards Practical Asymmetric
Multifunctional Catalysis
Shigeki Matsunaga, Takashi Ohshima, Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
Fax: ( ‡ 81)-3-5684-5206, e-mail: mshibasa@mol.f.u-tokyo.ac.jp
Received: May 31, 2001; Accepted September 8, 2001
Abstract: The development and application of a novel
linked-1,1'-binaphthol (linked-BINOL) as an approach
towards practical asymmetric multifunctional catalysis is
described. Linked-BINOL was first designed to increase the
stability of a Ga-Li-BINOL complex against ligand ex-
change with 4-methoxyphenol. An oxygen-containing
linked-BINOL, which is a semi crown ether, was effective
in both promoting the formation of a monomer complex and
increasing the stability of the Ga-Li complex. A Ga-Li-
linked-BINOL complex promoted the epoxide opening
reaction in up to 96% enantiomeric excess (ee). Second,
based on the X-ray structural information of the Ga-Li-
linked-BINOL complex, we designed a more stable lantha-
nide linked-BINOL complex. An air-stable, storable, and
reusable La-linked-BINOL complex promoted the Michael
reaction in up to >99% ee. The catalyst activity remained
unchanged after storage under air for 4 weeks. Calculations
suggested that the linked-BINOL would function as a
pentadentate ligand in a lanthanum complex, thus efficient-
ly improving the stability of the complex. Finally, the linked-
BINOL was applied to a new homobimetallic multifunc-
tional catalysis. A dinuclear Zn-Zn-linked-BINOL complex
promoted the enantio-and diastereoselective direct aldol
reaction in up to 99% ee, where one Zn cation might
function as a Lewis acid and the other Zn-phenoxide as a
Br˘nsted base.
1 Introduction
2 Heterobimetallic Multifunctional Asymmetric Complexes
3 Ga-Li-linked-BINOL Complex: Design and Develop-
ment of a Novel Linked-BINOL
4 La-linked-BINOL Complex: Development of Stable,
Storable and Reusable Asymmetric Catalyst for Catalytic
Asymmetric Michael Reaction
5 Zn-Zn-linked-BINOL Complex: A New Homobimetallic
Multifunctional Catalysis for the Practical Direct Aldol
Reaction
6 Conclusions
Keywords: asymmetric catalysis; BINOL; bridging ligands;
bimetallic complex; lanthanum; multifunctional catalysis.
1 Introduction
improvement, such as in catalyst amount and stability. To
overcome these problems and to widen the scope of multi-
functional bimetallic catalysis, we launched a new project for
the development of a novel chiral ligand. This review focuses
on our efforts towards the development and application of a
novel linked-BINOL, which opened up the new possibility of
multifunctional asymmetric catalysis.
Synthesis of chiral compounds using catalytic asymmetric
processes is one of the most important and most rapidly
growing areas in modern synthetic organic chemistry.[1] Such
catalytic and asymmetric processes are more economic and
more environmentally benign than processes that use stoichio-
metric amounts of reagents. In our continuing research project
towards the development of practical and atom-economic[2]
asymmetric catalysis, we have demonstrated the usefulness of 2 Heterobimetallic Multifunctional Asymmetric
multifunctional cooperative asymmetric catalysis in a variety
of enantioselective transformations,[3] such as the nitroaldol
reaction,[4] direct aldol reaction,[5] Michael reaction,[6] Michael-
aldol reaction,[7] hydrophosphonylation,[8] hydrophosphina-
tion,[9] protonation,[10] epoxidation of enones,[11] epoxide open-
ing reaction,[12] Diels À Alder reaction,[13] nitro-Mannich reac-
tion,[14] cyanosilylation of aldehydes[15] and ketones,[16] Strecker
reaction,[17] and Reissert reaction.[18] There have been great
achievements in the field of asymmetric catalysis with regard to
the concept of multifunctional cooperative catalysis, and many
groups are now employing a multifunctional strategy in the
development of new asymmetric catalysts.[19,20] From a prac-
tical point of view, however, some of the heterobimetallic
multifunctional asymmetric complexes still have room for
Complexes
1,1'-Binaphthols (BINOLs) have an important role as chiral
ligands in modern asymmetric catalysis,[21] incorporating
various types of Lewis acidic metals. Our heterobimetallic
complexes also consist of two or three BINOLs, Lewis acidic
central metals, and alkali metals, the structures of which were
unequivocally determined using NMR, LDI-TOF mass spec-
trometry, and X-ray crystal analysis (Figure 1).[22]
Mechanistic studies[22] suggest that the heterobimetallic
complexes promote the various asymmetric reactions via
dual activation of both substrates (nucleophiles and electro-
philes). The Br˘nsted base moiety of the catalysts (alkali metal
binaphthoxide) activates the nucleophiles, such as nitroal-
Adv. Synth. Catal. 2002, 344, No. 1
¹ VCH Verlagsgesellschaft mbH, D-69451 Weinheim, 2002 1615-4150/02/34401-003 015 $ 17.50+.50/0
3

Shigeki Matsunaga et al.
REVIEWS
Shigeki Matsunaga was born in
1975 in Kyoto, Japan. He earned
his B. S. degree in 1998 and M. S.
degree in 2000 with a thesis on a
novel chiral ligand, linked BI-
NOL, from the University of
Tokyo, where he continued his
doctoral work under the super-
vision of Professor Masakatsu
Shibasaki. In 2001, he began his
career as an assistant professor in
Professor Shibasaki×s group at
the University of Tokyo.
Lewis acid
M
O
O
Ln
O
O
O
O
O
O
O
M1
M2
M
O
M
Brønsted base
M1 = Al, M2 = Li : ALB 2
M1 = Ga, M2 = Li : GaLB 3
Ln = La, M = Li : LLB 1
Figure 1. Heterobimetallic multifunctional complexes.
kanes, by deprotonation. At the same time, the Lewis acid
moieties (lanthanides, aluminum or gallium center metals)
activate the electrophiles. The dual activation occurs at
positions controlled by the asymmetric catalyst, and so the
substrates react with the other substrates from a defined
direction, resulting in high enantioselectivity.
Takashi Ohshima was born in
1968 in Ehime, Japan and re-
ceived his Ph. D. from The Uni-
versity of Tokyo in 1996 under
the direction of Professor Masa-
katsu Shibasaki. On the following
Although the heterobimetallic complexes work well in
various asymmetric reactions,[3] the structural features of two
or more ligands incorporated in the complexes sometimes
cause a severe stability problem. In the worst cases, some
heterobimetallic complexes decompose under the reaction
conditions due to irreversible ligand exchange between
BINOLs and nucleophiles, resulting in a lower chemical yield
and/or enantiomeric excess of the desired products. For
example, we previously reported the enantioselective epoxide
opening reaction with 4-methoxyphenol promoted by the
GaLibis(binaphthoxide) (GaLB) complex (Figure 1, 3).[12b] In
this reaction, GaLB afforded enantiomerically enriched 1,2-
diol monoethers, which are versatile chiral building blocks, in
only moderate chemical yields despite the use of more than
20 mol % of the catalyst. The poor reactivity of GaLB 3 was
attributed to a ligand exchange between BINOL and 4-
methoxyphenol, and the preparation of a more stable Ga
complex was an effective solution to this problem. Thus, we
first attempted to increase the stability of the GaLB complex 3
through the development of new chiral ligands.
year, he joined Otsuka Pharma-
ceutical Co., Ltd. for one year.
After two years as a postdoctoral
fellow at The Scripps Research
Institute with Professor K. C.
Nicolaou (1997 1999), he returned to Japan and joined
Professor Shibasaki×s group in The University of Tokyo as
an assistant professor. He has received the Fujisawa
Award in Synthetic Organic Chemistry, Japan (2001).
Masakatsu Shibasaki was born in
1947 in Saitama, Japan, and re-
ceived his Ph. D. from the Uni-
versity of Tokyo in 1974 under
the direction of the late Professor
Shun-ichi Yamada before doing
postdoctoral studies with Profes-
sor E. J. Corey at Harvard Uni-
versity. In 1977 he returned to
Japan and joined Teikyo Univer-
sity as an associate professor. In
1983 he moved to Sagami Chemical Research Center as a
group leader, in 1986 to Hokkaido University as a
professor, and in 1991 to the University of Tokyo as a
professor. He was a visiting professor at Philipps-Uni-
versit‰t Marburg during 1995. He has received the
Pharmaceutical Society of Japan Award for Young
scientists (1981), the Inoue Prize for Science (1994), the
Fluka Prize (Reagent of the Year, 1996), the Elsevier
Award for Inventiveness in Organic Chemistry (1998), the
Pharmaceutical Society of Japan Award (1999), Molecular
Chirality Award (1999) and the Naito Foundation Re-
search Prize for 2001 (2001). He will receive ACS Arthur
C. Cope Senior Scholar Award in 2002. His research
interests include asymmetric catalysis, including asym-
metric Heck reactions and reactions promoted by asym-
metric bifunctional complexes, and also the medicinal
chemistry of biologically significant compounds.
3 Ga-Li-linked-BINOL Complex: Design and
Development of a Novel Linked-BINOL
To increase the stability of the GaLB 3, we hypothesized that
by linking the two BINOL units in GaLB, the complex would
become more stable against ligand exchange without any
adverse effects on the asymmetric environment.[23,24] One of
the key issues for designing a linked-BINOL is the length and
flexibility of its linker. The linker should be relatively short to
somewhat limit the flexibility of BINOL units, because the
geometry is likely to be crucial for enantioselectivity. In
addition, a linker that is too rigid would also be unfavorable,
because the asymmetric environment would be negatively
affected by a rigid linker and, in the worst cases, even the
formation of the desired 1:2 (gallium:BINOL unit) complex
would be prevented.
4
Adv. Synth. Catal. 2002, 344, 3 15

Linked-BINOL: An Approach towards Practical Asymmetric Multifunctional Catalysis
REVIEWS
Y
CHO
Y
−CH2−
4:
(a, b)
73%
(c)
−(CH2)2−
OH
OH
OH
OH
HO
HO
5:
OMOM
OMOM
−(CH2)3−
6:
−CH OCH −
10:
2
2
Figure 2. Carbon-linked-BINOLs (4 6) and linked-BINOL (10).
11
12
OH
Br
(d)
OMOM
OMOM
OMOM
OMOM
We first designed carbon-linked-BINOLs (Figure 2, 4 6) to
evaluate the effect of the linker. We prepared Ga-Li-carbon-
linked-BINOL complexes using GaCl3 (1 mol eq), 4, 5, or 6
(1 mol eq), and BuLi (4 mol eq). In contrast to our initial
assumption, however, none of these were effective in the
enantioselective epoxide opening reaction of cyclohexene
oxide (7a) with 4-methoxyphenol (8). Ga-Li carbon-linked-
BINOL complexes afforded the epoxide opening product 9a in
only low yield and enantiomeric excess (with 4: yield 28%, 27%
ee; with 5: yield 43%, 10% ee; with 6: yield 40%, 1% ee). These
unsatisfactory results might be due to the undesired oligomeric
structure of these linked-BINOL complexes. With a carbon
linker, each BINOL unit of the linked-BINOLs can rotate
freely during the formation of Ga complexes. As shown in
Figure 3, the conformation (A) seems favored due to the steric
and electronic repulsion, thus the Ga-Li-carbon-linked-BINOL
would result in undesired oligomeric species, the asymmetric
environment of which should be different from that of the
monomeric GaLB 3.
To overcome this problem, we designed a novel oxygen-
containing linked-BINOL (Figure 2, 10). This new linked-
BINOL 10 was designed based on reports by Cram et al.
regarding crown ethers incorporating chiral-BINOL units.[25]
We assumed that the oxygen atom in the linker would
coordinate to gallium during the Ga complex formation, thus
helping the formation of the desired monomeric Ga complex.
In contrast to crown ether-type cyclic ligands, this linked-
BINOL, which is a kind of semi-crown ether linked only with
one side of the BINOL units (3 3'' position), has a vacant
coordination site around the gallium center metal. Thus, the
Ga-Li-linked-BINOL complex should be active as a Lewis acid
towards epoxides. The preparation of 10 is shown in Scheme 1.
93%
from 12
14
13
O
OH HO
OH HO
(e, f)
70%
10
(a) NaH, MOMCl, DMF, 0 °C, 5 h; (b) i) BuLi, TMEDA, THF, −78 °C
to 0 °C; ii) DMF, −78 °C to 0 °C; (c) NaBH4, THF, MeOH, 0 °C, 15
min; (d) i) MsCl, toluene, AcOEt, 0 °C, 90 min; ii) LiBr, DMF, rt, 10
min; (e) i) NaH, THF, DMF, 0 °C, 60 min; ii) 14, rt, 64 h; (f)
TsOH−H2O, CH2Cl2, MeOH, 40 °C, 36 h.
Scheme 1. Synthesis of the oxygen-containing (R,R)-linked-BI-
NOL 10.
Starting from optically active (R)-BINOL,[26] the (R,R)-linked-
BINOL 10 was obtained easily on a gram scale [7 steps, total
yield 47% from (R)-BINOL].
Complex 15 [prepared from GaCl3 (1 mol eq), 10 (1 mol eq),
and BuLi (4 mol eq): Scheme 2] was far more stable than
GaLB 3, and very effective for the epoxide opening reaction.
The results are summarized in Table 1. Unlike GaLB, complex
15 was stable even in the presence of excess 4-methoxyphenol
(8) and/or at higher temperature. By using complex 15, the
reaction proceeded smoothly with reduced levels of catalyst for
the first time. Under optimized conditions (toluene, 758C, 3 eq
of 8), cyclohexene oxide (7a) reacts with 4-methoxyphenol (8)
smoothly in the presence of 10 mol % catalyst, half the amount
of GaLB, to afford 9a (36 h, yield 94%, 85% ee, entry 4).
Entries 1 through 5 show that the new catalyst 15 (10 mol %)
afforded products (9a 9e) in analogous enantiomeric excess
O
O
1)
2)
Ga
BuLi
O
(4 mol eq)
O
O
O
O
Li
carbon-linked-BINOL
3 LiCl
Ga
Li
4, 5 or 6
Y
GaCl3
(1 mol eq)
O
O
O
O
Ga
Li
(R,R)-Ga-Li linked BINOL 3 LiCl complex 15
BuLi
Y
LiO
LiO
O
O
O
O
Ga
Li
O
1)
2)
Ga(O-i-Pr)3
O
O
O
O
Y
(1 mol eq)
Ga
Li
Y
10
(1 mol eq)
GaCl3
BuLi
(1 mol eq)
OLi
OLi
O
O
Ga
(A)
LiCl-free (R,R)-Ga-Li linked BINOL complex 16
Scheme 2. Preparation of (R,R)-Ga-Li-linked-BINOL ¥ 3 LiCl
complex 15 and the LiCl-free (R,R)-Ga-Li-linked-BINOL com-
plex 16.
Figure 3. Possible oligomeric structure of Ga-Li carbon-linked-
BINOL complexes.
Adv. Synth. Catal. 2002, 344, 3 15
5

Shigeki Matsunaga et al.
REVIEWS
Table 1. Enantioselective ring opening of various meso-epoxides with 4-methoxyphenol (8) promoted by the Ga-Li-linked-BINOL complex (15) and
GaLB (3).
R
(R)OH
R
R
(R,R)-Ga complex
toluene, MS 4 Å
+
O
HO
OCH3
: 8
R (R)
O
OCH3
9
ArOH
GaLB
Ga-Li-linked-BINOL
( 10 mol % )
( 20 mol % )
temp
(°C)
yield[a]
(%)
yield[a]
(%)
temp
product
time
(h)
entry
epoxide
O
ArOH
(eq)
ee[b]
(%)
ArOH
(eq)
time
(h)
ee[b]
(%)
(°C)
1[c]
2
7a
9a
9b
3.0
3.0
3.0
75
60
96
63
72
88
91
1.2
1.2
50
72
72
48
75
93
86
O
O
7b
85
50
3
4
5
7c
7d
9c
9d
75
75
108
36
82
94
66
85
1.2
1.2
50
50
72
72
31
74
67
87
3.0
(1.2)[d]
O
(75)[d](117)[d] (80)[d] (91)[d]
SPDBTO
SPDBTO
O
7e
7f
9e
9f
3.0
60
96
160
48
72
79
1.2
1.2
−
50
50
−
96
160
−
34
80
6
7
O
O
77[e] 78[e]
51[e] 90[e]
Mts
N
3.0
60
TBSO
7g
7h
9g
9h
−
−
−
−
3.0
2.0
60
60
67
85
87
96
OCH3
O
O
8
70
−
−
−
OCH3
H3C
7i
9i
−
−
−
−
−
3.0
60
140
72
91
9
H3C
[a] Isolated yield.
[b] Determined by HPLC analysis.
[c] The reaction was run on 0.5 mmol scale at 0.25 M in epoxide.
[d] 3 mol % of catalyst was used.
[e] 30 mol % of catalyst was used. Mts = 2,4,6-trimethylbenzenesulfonyl.
(66 91%) but in much higher chemical yields (72 94%)
compared to GaLB (20 mol %, Table 1). After the reaction
ligand 10 was recovered by extracting with 1M aqueous NaOH.
This situation was very different from that with GaLB 3
because BINOL itself reacted with epoxide and the recovery of
BINOL was impossible. The Ga-Li-linked-BINOL 15 was also
effective for epoxides 7g 7i (entries 7 9). Importantly, using
only 3 mol % of catalyst 15, epoxide 7d gave 9d in 80% yield
(TON ˆ 26.3) and 91% ee, however the reaction time was long
(117 h, entry 4 in parenthesis). All of these results can be
attributed to the stability of the Ga-Li-linked-BINOL complex
15, obtained by linking the two BINOL units in GaLB 3. The
stable catalyst 15 remained unchanged during the course of the
reaction, whereas GaLB 3 decomposed due to severe ligand
exchange with 4-methoxyphenol (8) and the reaction then
stopped.
prepared from GaCl3, were unsuccessful. After several trials,
we obtained X-ray grade crystal of the LiCl-free Ga-Li-linked-
BINOL complex 16, prepared from Ga(O-i-Pr)3 (1 mol eq),
linked-BINOL 10 (1 mol eq), and BuLi (1 mol eq) (Scheme 2).
The LiCl-free Ga-Li-linked-BINOL complex 16 also promot-
ed the reaction to give 9a in good yield (85%), although the
enantiomeric excess (74%) was somewhat lower. As shown in
Figure 4, Ga-Li-linked-BINOL complex has a monomeric
tetracoordinated structure, which is similar to the structure of
the Al-Li-bis(binaphthoxide)(thf)3 complex (ALB: 2 in Fig-
ure 1).[6a] The crystal structure clearly indicates that, as planned
initially, the linked-BINOL has no adverse effects on the
asymmetric environment constructed by the two BINOL units
in GaLB 3. Instead, the linked-BINOL 10 provides stability
against ligand exchange by linking the two BINOL units. On
the other hand, in contrast to our initial assumption, the oxygen
atom in the linker does not coordinate to the gallium metal
center, at least in the ground state. The different results
obtained by carbon-linked-BINOL 6 (9a, 1% ee) and linked-
BINOL 10 (9a, 91% ee) indicate that the oxygen in the linker
should have a key role in the present system. The oxygen in the
linker might provide properties similar to a crown ether to the
ligand, thus promoting formation of the desired monomeric
species similar to GaLB 3 during the complex formation.
The proposed mechanism of the epoxide opening reaction
with 4-methoxyphenol (8) is shown in Scheme 3. The gallium
Having improved stability of the Ga-Li complex against
ligand exchange with the newly developed linked-BINOL 10,
we then attempted to determine the structure of the linked-
BINOL complex because the structural information should
provide clues for applying the linked-BINOL 10 to other
catalytic asymmetric reactions. Although both 13C NMR and
(
)-LDI TOF mass spectrometry [Ga-Li-linked-BINOL 15:
‡
(M Li ) ˆ 679 for 69Ga (base peak)] data suggested the
assumed monomeric structures, all attempts to obtain X-ray
grade crystals of the Ga-Li-linked-BINOL complex 15,
6
Adv. Synth. Catal. 2002, 344, 3 15

Linked-BINOL: An Approach towards Practical Asymmetric Multifunctional Catalysis
REVIEWS
coordinating to gallium would be fixed in the (A) form rather
than the (B) form. Lithium binaphthoxide then activates and
controls the orientation of 4-methoxyphenol (8: ArOH) so that
lithium phenoxide attacks the epoxide selectively from one
side to afford the (R,R)-1,2-diol monoether.
4 La-linked-BINOL Complex: Development of
Stable, Storable and Reusable Asymmetric
Catalyst for Catalytic Asymmetric Michael
Reaction
Thedevelopmentof efficient methods to facilitatethe recovery
and reuse of asymmetric catalysts remains an important goal in
organic chemistry. To address this issue, intensive efforts have
been devoted to develop soluble and insoluble polymer-
supported asymmetric catalysts.[27,28] Only a few reusable
non-polymer-supported homogeneous asymmetric cata-
lysts[29] have been developed, however, due to the difficulty
of recovery for recycling. In the previous section, we demon-
strated that the linked-BINOL 10 effectively stabilized the Ga-
Li complex against ligand exchange with a nucleophile under
the reaction conditions.[23a] In terms of catalyst stability,
however, group XIII metal complexes such as Al and Ga
complexes are still unsatisfactory for recovery and reuse
because of their high reactivity to moisture.[30]
Figure 4. X-ray structure of LiCl-free Ga-Li-linked-BINOL 16.
metal center acts as a Lewis acid and activates epoxides (I),
while at the same time the lithium binaphthoxide moiety
functions as a Br˘nsted base to activate 4-methoxyphenol (8:
ArOH) (II). The activated nucleophile would then react with
epoxide to give III. Proton exchange between gallium alkoxide
and an aromatic hydroxy proton leads to the epoxide opening
adduct and regeneration of the catalyst. On the basis of the X-
ray structure of LiCl-free (R,R)-Ga-Li-linked-BINOL com-
plex 16 and the absolute configuration of the product obtained
using this catalyst [(R,R)-9a], enantiomeric induction in the
present system is explained by assuming the transition state
shown in Figure 5. Due to the steric hindrance, the epoxide
To develop more stable, even against moisture, asymmetric
catalysts, we examined a combination of rare earth metals
(lanthanides: Ln) and the linked-BINOL 10. We expected that
rare earth metals would be useful as Lewis acidic metal centers
in the linked-BINOL complex. This combination (Ln-M-
linked-BINOL) should lead to much more stable complexes,
considering the following aspects. (1) The Ln phenoxide
complex is relatively stable against moisture.[31] (2) The ionic
radius and coordination number of lanthanides are larger than
that of gallium (Ga3‡: ionic radius 61 76 pm, coordination
number 4 6, La3‡: ionic radius 103 136 pm, coordination
number 6 12).[32] Thus, in contrast to the LiCl-free Ga-Li-
linked-BINOL complex 16 (Figure 4), the oxygen in the linker
is likely to coordinate to the rare earth metal in an Ln-M-
linked-BINOL complex, and linked-BINOL 10 might function
as a pentadentate ligand (Figure 6). To evaluate this hypoth-
esis, we performed computational optimization of the Ln-
linked-BINOL complex. On the basis of the structure of the
Ga-Li-linked-BINOL complex 16, a model compound (La
linked biphenol complex) was computationally optimized.
O
O
O
O
O
OH
Ga
*
*
O
OAr
Li
*
Lewis acid
O
Ga
O
O
O
O
O
O
O
O
O
*
Ga
*
*
O
Li
H
Brønsted base
O
Li
OAr
O
I
III
O
O
O
O
Ga
O
*
*
ArOH
H
Li
OAr
II
Scheme 3. Working model for the ring opening of cyclohexene
oxide with 4-methoxyphenol (8: ArOH) catalyzed by Ga-Li-
linked-BINOL complex.
O
O
O
O
O
Ga
O
Ga
O
O
H
H
O
O
O
O
Li
O
Li
O
O
O
O
O
Ar
Ln
M
O
Ar
(B) disfavored
(A) favored
ionic radius
coordination site
OH
OH
103 − 136 pm
61 − 76 pm
La
6 − 12
4 − 6
OAr
OAr
Ga
(R,R)
(S,S)
Figure 5. Working transition state model for meso-epoxide open-
ing reaction promoted by Ga-Li-linked-BINOL (15).
Figure 6. Expected structure of (R,R)-Ln-M-linked-BINOL com-
plex.
Adv. Synth. Catal. 2002, 344, 3 15
7

Shigeki Matsunaga et al.
REVIEWS
First, the initial structure of the La-linked-BINOL complex
was obtained by substitutions of the center metal (from Ga to
La) and the counter cation of the phenolic oxygen (from Li to
H) in the Ga-Li-linked-BINOL complex 16. The lowest energy
conformation of La-linked-BINOL was obtained by using
several conformational search methods followed by molecular
mechanics minimization [UNIVERSAL forcefield[33] (v. 1.02)
calculation performed on Cerius2 (Molecular Simulations
Inc.)]. Next, the initial structure of the La-linked biphenol
complex was obtained by simplifying the optimized structure
of the La-linked-BINOL complex. The geometry optimization
of the La-linked biphenol complex to minima was performed
using ab initio calculation [HF/LanL2DZ[34] level with Gaus-
sian 98[35] (Gaussian Inc.)]. Although the optimization did not
reach a stationary point due to the high flexibility of La-linked
biphenol, the distance between lanthanum and oxygen in the
linker ranged from 262 to 269 pm after nine calculation steps
(Figure 7). The result indicated that the distance between
lanthanum and oxygen in the linker should be nearly equal to
that between lanthanum and phenolic oxygen (258 265 pm).
As we expected, the oxygen atom in the linker could also
function as a coordinative moiety and thus, the linked-BINOL
10 could function as pentadentate ligand toward lanthanum.
In recent years, the catalytic asymmetric Michael reaction
promoted by chiral metal complexes has been recognized as an
efficient method for enantioselective carbon-carbon bond
formations. Although efficient catalytic asymmetric Michael
reactions have been achieved by our group[3d,6,7,36] and oth-
ers,[37 39] there is still a big demand for improvement in terms of
generality and stability of the catalyst. For example, AlLibis-
(binaphthoxide) complex (ALB: 2)[7] is applicable only to
cyclic enones and is also moisture sensitive.[30,40] Thus, we
attempted to increase the stability of the ALB complex 2. For
preparation of an efficient linked-BINOL complex, lanthanum
was chosen as a Lewis acidic metal center instead of aluminum
based on the above-mentioned negative factors of group XIII
metals. First, an asymmetric Michael reaction of 2-cyclohexen-
1-one (17) with dibenzyl malonate (18) was examined with
monometallic (La only) and heterobimetallic (La-Li, La-Na,
La-K) complexes. The results are summarized in Table 2. The
best result was obtained using alkali-metal free La-linked-
BINOL complex 20 (entry 4), in which lanthanum metal
should function as a Lewis acid and the lanthanum naphthox-
ide moiety should function as a Br˘nsted base to promote the
reaction. The proposed mechanism of the catalytic asymmetric
Michael reaction of enones with malonates using the La-
linked-BINOL complex 20 is shown in Scheme 4. After
optimization of the reaction conditions, we finally found that
the use of DME as a solvent afforded 19 in 94% yield and
>99% ee at room temperature (Table 2, entry 5).[41]
Next, we examined the scope and limitations of different
substrates. In all cases, the reaction was run at 0.4 M in enone
and malonate. As shown in Table 3, the complex 20 promoted
the Michael reaction of a variety of cyclic enones (from 5- to 9-
membered rings!) with various malonates to afford Michael
adducts with good to excellent enantiomeric excess. The
Table 2. Catalytic asymmetric Michael reaction promoted by (R,R)-La-
M-linked-BINOL complexes.
O
O
O
O
O
La
M
O
O
CO2Bn
(10 mol %)
+
CO2Bn
CO2Bn
CO2Bn
17
18
19
yield (%)[a]
ee (%)[b]
entry
solvent temp. (°C) time (h)
M
21
41
16
53
94
Li
1
2
3
4
5
THF
THF
THF
THF
DME
0
0
24
24
24
45
72
35
43[c]
54[c]
85
Na
K
−20
0
H (20)
H (20)
rt
>99
[a] Isolated yield.
[b] Determined by HPLC analysis.
[c] The mirror image enantiomer was formed.
O
O
O
O
O
(RO2C)2HC
O
O
La
*
*
H
20
Lewis Acid
*
Brønsted Base
O
O
O
O
O
O
O
O
O
La
O
La
*
*
*
O
H
H
O
H
(RO2C)2HC
O
O
O
O
La
*
*
O
H
O
H
O
O
O
O
RO
OR
RO
OR
Figure 7. Computational optimization of La-linked-BINOL com-
plex.
Scheme 4. Proposed mechanism for the Michael reaction of
enones with malonates.
8
Adv. Synth. Catal. 2002, 344, 3 15

Linked-BINOL: An Approach towards Practical Asymmetric Multifunctional Catalysis
REVIEWS
Table 3. Catalytic asymmetric Michael reactions promoted by (R,R)-La-
linked-BINOL 20.[a]
O
O
CO2R1
CO2R1
20 (10 mol %)
R2
CO2R1
CO2R1
+
DME
n
n
R1 = Bn, R2 = H: 18
R1 = Me, R2 = H: 25
R1 = Bn, R2 = Me: 26
R2
19, 27-34
n = 0: 21
n = 1: 17
n = 2: 22
n = 3: 23
n = 4: 24
Figure 8. Preparation of the stock air-stable powdered (R,R)-La-
linked-BINOL complex 20.
O
Me
O
18
20 (10 mol %)
DME
CO2R1
or
+
Ph
25
Ph
Me
+
36, 37 CO2R1
35
Table 4. Catalytic asymmetric Michael reaction promoted by stock (R,R)-
La-linked-BINOL complex 20.
O
O
CO2Et
CO2Et
O
O
O
20 (10 mol %)
(R,R)-La-linked-BINOL
complex 20 (10 mol %)
CO2Bn
toluene
+
CO2Bn
CO2Bn
38
39
40
CO2Bn
O
[b] ee[c]
DME, 4 °C, 110 h
time
temp.
entry
enone β-dicarbonyl
product yield
(%)
17
18
19
(h)
(%)
(°C)
compounds
storage time (week)[a]
yield (%)[b]
1
2
85 >99
96 >99
94 >99
98 >99
95 >99
21
18
21
25
17
18
17
18
17
25
17
26
22
18
22
25
23
25
24
18
35
18
35
25
85
85
72
85
72
84
85
85
96
120
56
56
36
27
28
19
19
29
30
31
32
33
34
36
37
40
4
4
rt
4
rt
rt
4
4
rt
4
0
1
2
3
4
94
93
94
94
95
3
ee (%)[c]
>99
>99
>99
>99
>99
4
[a] (R,R)-La-linked-BINOL complex 20 was stored under air.
[b] Isolated yield.
5
6[d]
7
84
98
[c] Determined by HPLC analysis.
96 >99
97 >99
8
9[d]
10
11
12
13[e]
82
61
97
95
97
99
82
78
74
75
−40
enantiomeric excess, using stock catalyst. After 4 weeks
storage, 19 was obtained in 95% yield and >99% ee.
−40
−30
38
39
Finally, we succeeded in the recovery and reuse of the La-
linked-BINOL 20 from the reaction mixture by utilizing the
large difference in solubility between the complex 20 and
product 19. The successful implementation of this strategy is
shown in Figure 9. After completion of the reaction [A], the
complex 20 was precipitated by the addition of pentane at 08C
[B]. Supernatant liquid, which contained product 19 and only
trace amounts of 20, was simply separated via cannula [C], [D].
The residual precipitate was dried under reduced pressure to
afford the powdered complex 20 again [E].[43] After treatment
with THF, the recovered La-linked-BINOL complex 20 was
reused several times (Table 5). Although there was some loss
of activity, the recovered complex 20 promoted the Michael
reaction to afford the desired product 19 in very high
enantiomeric excess, even after the fourth use.
The structure of La-linked-BINOL 20 has not yet been
clarified. Instead, an X-ray crystal structure analysis of the
La(binaphthoxide)2(Ph3As ˆ O)3 complex 41 was recently
achieved,[11] which was the first X-ray analysis of an alkali
metal-free lanthanoid BINOL complex (Figure 10). We be-
lieve that the La-linked-BINOL 20, which also consists of La
and two BINOL units, may have a structure related to the
La(binaphthoxide)2(Ph3As ˆ O)3 complex 41. Studies eluci-
dating the structure of the La-linked-BINOL 20 are currently
in progress.
[a] In all cases, the reaction was run on 0.6 mmol scale at 0.4 M in
enone and malonate.
[b] Isolated yield.
[c] Determined by HPLC analysis.
[d] The reaction was carried out in DME/THF (9:1).
[e] 24 was added dropwise over 24 h.
complex 20 was also effective for the Michael reaction of
acyclic enones such as 35 with 18 (97%, 78% ee) and 25 (95%,
74% ee). In addition, the Michael reaction of 38 with 39 gave 40
in 97% yield and 75% ee, where a newly formed chiral center
was induced by the Michael donor moiety.[6b] To the best of our
knowledge no efficient catalytic Michael reaction of 8-and 9-
membered ring enones with malonates has been reported and
this is the first example of a Michael reaction where the catalyst
has such broad generality.
The novel La-linked-BINOL complex 20 was very stable
even in air and storable over a long time, probably because the
linked-BINOL 10 can function as pentadentate ligand toward
lanthanum. The complex 20 was easily prepared from La(O-i-
Pr)3[42] and 1.0 equivalent of the linked-BINOL 10, which were
mixed in THF followed by removal of the solvent under
reduced pressure to afford 20 as a pale-yellow powder, which
has no deliquescent properties (Figure 8). This air-stable
complex 20 is storable without any care at ambient temper-
ature for at least 4 weeks. As shown in Table 4, there was no
change in catalytic activity in terms of either chemical yield or
In this section, the successfulextension of the linked-BINOL
10 to the lanthanide complex to achieve an air-stable, storable,
and reusable asymmetric catalyst was described.[41] These
results suggest that the linked-BINOL 10 is flexible enough to
incorporate metals with various ionic radii like Ga (61 pm) and
Adv. Synth. Catal. 2002, 344, 3 15
9

Shigeki Matsunaga et al.
REVIEWS
Figure 9. Experimental procedure for catalytic asymmetric Michael reaction with catalyst recycling.
Table 5. Catalytic asymmetric Michael reaction with catalyst recycling.
O
O
O
O
(R,R)-La-linked-BINOL
complex 20 (10 mol %)
CO2Bn
O
O
O
O
La
M
+
CO2Bn
CO2Bn
CO2Bn
DME, 4 °C, 110 h
17
18
19
O
M = H: polymer-supported La-linked-BINOL 42
cycle
1
2
3
4
M = ZnEt: polymer-supported La-Zn-linked-BINOL 43
yield (%)[a]
ee (%)[b]
82
94
68
99
50
98
Figure 11. Polymer-supported La-linked-BINOL complex 42 and
La-Zn-linked-BINOL complex 43.
>99
>99
[a] Isolated yield.
[b] Determined by HPLC analysis.
investigating the La-linked-BINOL complex, we also exam-
ined the immobilization of the La-linked-BINOL complex 20
to an insoluble polymer. Although there was a severe decrease
in reactivity and selectivity with polymer-supported La-linked-
BINOL complex 42, the use of a new polymer-supported La-
Zn-linked-BINOL complex 43 (Figure 11) improves reactivity
in the Michael reaction.[44] A homogeneous La-Zn-linked-
BINOL complex was also effective in the Michael reaction of
cyclic enones with malonates to afford products in good
enantiomeric excess.[44] In the case of La-Zn-linked-BINOL
complex, the Zn-naphthoxide moiety is considered to function
as a Br˘nsted base. The use of mild and selective Zn species
finally led to the development of a new multifunctional
asymmetric catalysis, which will be discussed in the next
section.
Figure 10. X-ray structure of La(binaphthoxide)2(Ph3As ˆ O)3.
5 Zn-Zn-linked-BINOL Complex: A New
Homobimetallic Multifunctional Catalysis for the
Practical Direct Aldol Reaction
La (103 pm).[32] Application of the linked-BINOL 10 to other
Lewis acidic metals to increase their stability is under inves-
tigation in our group.
We now have two types of practical asymmetric multifunc-
tional catalysts for the Michael reaction of cyclic enones. (1)
ALB (Figure 1, 2) is suitable for large-scale synthesis on
account of its cost efficiency, reaction temperature (room
temperature), and catalyst loading (0.3 1 mol %, TON ˆ up
to 313) as well as chemical yield and enantiomeric excess,
although one should avoid moisture.[36a,40] (2) On the other
hand, La-linked-BINOL 20 requires rather high catalyst
loading (10 mol %, TON ˆ 9.7), but is suitable for small,
laboratory-scale synthesis, because La-linked-BINOL 20 is
stable, storable under air, and is very easy to handle.[41] While
The aldol reaction is generally regarded as one of the most
powerful and efficient carbon-carbon bond forming reactions.
Many efforts have been devoted to develop catalytic asym-
metric aldol reactions,[45] but almost all of these reactions
require preconversion of the ketone or ester moiety into a
more reactive species such as an enol silyl ether or a ketene silyl
acetal by using no less than stoichiometric amounts of bases
and reagents like (CH3)3SiCl. For the development of practical,
economic, and environmentally benign processes, it is ideal to
perform the aldol reaction with unmodified ketones and
aldehydes using only catalytic amount of reagents. Our success
10
Adv. Synth. Catal. 2002, 344, 3 15

Linked-BINOL: An Approach towards Practical Asymmetric Multifunctional Catalysis
REVIEWS
Table 6. Direct aldol reaction of various aldehydes with 2-hydroxyaceto-
phenone (44a).[a]
in performing direct catalytic asymmetric aldol reactions with
unmodified ketones[4] has attracted much interest in this
O
OH
O
potentially advantageous strategy, especially in terms of atom
(S,S)-catalyst 45
[46a, 46b]
economy.[2] List,
Barbas,[46a,46c] and Trost[20f] have also
+
RCHO
46
10 mol %
R
reported direct asymmetric aldol reactions using amino acids
or a chiral semi-crown Zn complex as catalysts. Moreover,
several groups recently reported enantio-and diastereoselec-
tive direct aldol reactions using biological-type catalysts[47] or
small molecular catalysts,[48,49] which considerably widened the
scope of the field. We also reported an enantio-and diaster-
eoselective direct aldol reaction with 2-hydroxyacetophenone
(44a), which provided anti-a,b-dihydroxy ketones using a
LaLi3tris(binaphthoxide) ¥ KOH (LLB ¥ KOH) complex
(Figure 12 and Scheme 5).[50] We hypothesized that a unique
property inherent in the linked-BINOL 10 would also provide
an effective direct aldol reaction.
OH
44a (2.0 eq)
OH
47
THF, −40 °C
Ph3P=O (20 mol %)
dr[c]
(syn/anti)
yield[b]
(%)
ee[d]
entry
product
time
(h)
R
(syn/anti)
47a
47b
47d
47e
47h
48
89
72/28
81/81
1
Ph
(48)[e] (81)[e] (67/33)[e] (78/76)[e]
46a
46b
46d
2
3
4
5
6
7
60
36
80
80
67/33
67/33
67/33
83/17
77/73
83/79
79/75
86/67
81
92
60
36
Many catalysts, such as Ln-linked-BINOL (Ln ˆ La, Gd, or
Yb)[41] and Ln-Zn-linked-BINOL (Ln ˆ La, Gd, Y, or Yb), [44]
were examined and a new homobimetallic (S,S)-Zn-Zn-linked-
BINOL complex 45 prepared from linked-BINOL and 2
equivalents of Et2Zn (Figure 12) showed promising results.[50,51]
Although the structure of 45 has not yet been clarified, we
propose the ate complex depicted as [Zn(OAr)4]2ÀZn2‡
(Figure 12) based on the property of this semi-crown ether
type ligand and the X-ray structure of the Ga-Li-linked-
46e
46h
47i
47j
48
48
79
89
88/12
85/15
79/72
85/78
46i
46j
[a] All reactions were run on 0.3 mmol scale at 0.15 M in aldehyde.
[b] Isolated yield after conversion to acetonides.
[c] Determined by 1H NMR of crude mixture.
[d] Determined by chiral HPLC.
‡
BINOL complex ([Ga(OAr)4]ÀLi ). Attempts to obtain X-ray
grade crystals of Zn-Zn-linked-BINOL are currently under-
way in our laboratory. After optimization of the reaction
conditions, the syn-aldol 47a was selectively obtained in a ratio
of 2 (syn, 81% ee) to 1 (anti, 81% ee) on treatment of 3-
phenylpropanal (46a) with 2-hydroxyacetophenone (44a,
2 equiv.) in the presence of 45 (10 mol %) and triphenylphos-
phine oxide (20 mol %; entry 1, Table 6). As shown in Table 6,
the reaction of 44a with a variety of aldehydes afforded the
[e] In the absence of Ph3P(O).
corresponding syn-aldols 47 stereoselectively in moderate to
good enantiomeric excess.
From a practical perspective, there remains much room for
improvement in the present reaction with respect to catalyst
amount (10 mol %), diastereomeric ratio (syn/anti ˆ 67/33 to
88/12), enantiomeric excess (77 86% for syn isomer), reaction
rate, and yield. Our previous results suggested that substituents
on the aromatic ring of acetophenones should affect both
diastereoselectivity and enantioselectivity.[5b] We chose me-
thoxy-substituted acetophenones, based on the following: from
a synthetic point of view, the use of aryl ketones is potentially
advantageous over the use of dialkyl ketones such as acetone
and hydroxyacetone, because the aromatic ring functions as a
placeholder for further conversions via regioselective rear-
rangements. Electron-rich methoxy-substituted acetophe-
nones facilitates conversions such as a BaeyerÀ Villiger
oxidation.
KOH
O
Li
O
O
O
O
O
O
O
Li La
O
Zn
Zn
O
Li
O
1 KOH
45
Figure 12. (S)-LaLi3tris(binaphthoxide) ¥ KOH (LLB ¥ KOH)
complex 1 ¥ KOH and (S,S)-Zn-Zn-linked-BINOL complex 45.
We investigated the direct aldol reaction of 3-phenylpropa-
nal (46a) using methoxy-substituted 2-hydroxyacetophenones
44b 44d. The aldol adducts were isolated after their con-
version into the corresponding acetonides. As shown in
Table 7, the reaction rate, yield, diastereomeric ratio, and
enantiomeric excess all were improved when using 2-hydroxy-
2'-methoxyacetophenone (44d) (entry 4). In contrast to 44a,
Ph3P(O) as an additive had no positive effects (entry 5). It is
noteworthy that the aldol reaction of 44d still proceeded
smoothly even when the catalyst amount was reduced. The
reaction was completed within 4 h with 3 mol % of catalyst 45
OH
O
X
X
R
RCHO
R
R
S
(S)-LLB KOH (1 KOH)
or
(S,S)-Zn-Zn-linked-BINOL 45
46
OH
(2R,3S)-syn
+
O
OH O
THF
X
R
R
OH
44a: X = H
OH
(2R,3R)-anti
Scheme 5. General scheme for direct aldol reaction with
hydroxyacetophenones.
Adv. Synth. Catal. 2002, 344, 3 15
11

Shigeki Matsunaga et al.
REVIEWS
Table 7. Direct aldol reaction of 46a with methoxy-substituted 2-hydro-
xyacetophenone 44 catalyzed by (S,S)-Zn-Zn-linked-BINOL 45.[a]
Table 8. Direct aldol reaction of various aldehydes with 2×-methoxy-2-
hydroxyacetophenone (44d).[a]
CHO
Ph
O
OMe
OH
O
OMe
(S,S)-catalyst 45
OH
O
46a
+
+
RCHO
(S,S)-catalyst 45
1 mol %
R
X
R
O
Ph
OH
44d (2.0 eq)
OH
48
S
THF
X
THF, −30 °C
OH
46
OH
entry
44 (2.0 eq.)
catalyst temp. time yield[b] dr[c]
(mol %) (°C) (h) (%) (syn/anti)(syn/anti)
dr[c]
(syn/anti) (syn/anti)
time
(h)
yield[b]
(%)
ee[d]
product
entry
1
R
ee[d]
X
48a
48b
48c
48d
48e
48f
20
18
18
18
24
18
16
24
16
18
94
88
84
84
94
81
84
83
92
95
89/11
88/12
87/13
84/16
86/14
86/14
72/28
97/3
92/89
95/91
96/87
93/87
87/92
95/90
96/93
98/—
99/—
98/—
Ph
H
44a
44b
44c
44d
44d
44d
44d
44d
1
2
3
4
5
6
7
8
10
10
10
10
10
3
−40
−20
−30
−30
−30
−30
−30
−30
48
24
12
3
81
73
85
93
93
94
94
94
67/33
60/40
70/30
89/11
86/14
90/10
89/11
87/13
78/76
86/86
77/77
86/88
86/77
90/89
92/89
93/91
46a
46b
46c
46d
46e
46f
4'-MeO
3'-MeO
2'-MeO
[e] 2'-MeO
2'-MeO
2'-MeO
2'-MeO
2
3
3
4
4
1
20
16
1
5
[a] Reactions were run on 0.30 mmol scale (entries 1 - 5), 0.67 mmol
scale (entry 6), 1.0 mmol scale (entry 7), and 8.0 mmol scale (1.05 g
of 46a, entry 8) at 0.2 M in aldehyde.
[b] Isolated yield after conversion to acetonides.
[c] Determined by 1H NMR of crude mixture.
[d] Determined by chiral HPLC analysis of diols.
[e] In the presence of Ph3P(O) (20 mol %).
6
BnO
BnO
7
48g
48h
48i
46g
46h
46i
8
9
96/4
10
48j
97/3
(entry 6). Moreover, satisfactory yield (94%), diastereomeric
ratio (syn/anti ˆ 89/11), and enantiomeric excess (syn ˆ 92%,
anti ˆ 89%) were achieved after 20 h with as little as 1 mol %
of 45 (entry 7), and the reaction proceeded smoothly without
any problem on a gram scale (entry 8). To the best of our
knowledge, this is the most effective small molecular catalyst
for direct asymmetric aldol reactions in terms of catalyst
loading (TON ˆ 94). In combination with the successful gram-
scale experiment, the simple protocol proves the present
reaction to be practically useful. The catalyst was prepared by
just mixing commercially available Et2Zn in hexanes and easily
available linked-BINOL[23] in THF without any other addi-
tives, followed by the addition of ketone 44d and the aldehyde.
Zn-Zn-linked-BINOL 45 was also applicable to various
primary (a-unsubstituted) and secondary (a-monosubstitut-
ed) aldehydes (Table 8). In all cases, 1 mol % of catalyst 45 was
sufficient to complete the reaction within 24 h (TON ˆ 81 95).
Both normal (entries 1 3 and 5 7) and branched (entry 4)
primary aldehydes afforded good results (yield: 81 94%, dr:
syn/anti ˆ 72/28 to 89/11, ee: syn ˆ 87 96%, anti ˆ 87 93%).
It should be mentioned that primary (a-unsubstituted) alde-
hydes gave the corresponding aldol adducts in good to
excellent yields and enantiomeric excess without forming any
self-condensation products. The results demonstrate that the
present catalysis has high chemoselectivity. Remarkably,
secondary (a-monosubstituted) aldehydes (entries 8 10)
showed good yield (83 95%), excellent diastereomeric ratio
(syn/anti ˆ 96/4 to 97/3), and enantiomeric excess (98
99%).[52]
46j
[a] All reactions were run on 1.0 mmol scale at 0.2 M in aldehyde.
[b] Isolated yield after conversion to acetonides.
[c] Determined by 1H NMR of crude mixture.
[d] Determined by chiral HPLC analysis of diols.
the following reaction mechanism. The formation of a chelate
complex between the (S,S)-catalyst 45 and the enolate
generated from 44d results in an efficient shielding of the Si-
face of the enolate (Figure 13), so that both syn-and anti-aldol
adducts are obtained with an identical configuration at the a-
position (2R) after the attack towards the aldehyde.
Moreover, the electron donating substituent (methoxy
group) on the aromatic ring should increase the preference
of one chelate complex (shielding Si-face) to the other
(shielding Re-face) through participation of the 2×-methoxy
group in chelate formation (Figure 13). Thus, the Si-face
shielding would become more effective, resulting in higher
enantiomeric excess of both syn- and anti-products. On the
other hand, enhanced syn-selectivity is explained by the steric
hindrance of the aromatic ring in the enolate against aldehydes.
Considering the positions of the two Zn atoms in the proposed
structure of 45, it seems reasonable to assume that the enolate
coordinates to one Zn metal and the aldehyde coordinates to
the other in a manner as shown in (A) or (B) (Figure 13). The
transition state (A), which leads to syn-diols, is sterically more
favorable than (B). By using ketone 44d instead of non-
substituted 44a, the steric bias should increase, thus resulting in
the higher syn-selection. Detailed mechanistic studies are
currently in progress.
The observed stereoselectivity of the aldol adducts 48
[(2R,3S)-syn and (2R,3R)-anti from (S,S)-catalyst 45,
Scheme 5] obtained with ketone 44d is explained by assuming
12
Adv. Synth. Catal. 2002, 344, 3 15

Linked-BINOL: An Approach towards Practical Asymmetric Multifunctional Catalysis
REVIEWS
asymmetric catalysts. Further application of this homobime-
tallic system, especially to the efficient carbon-carbon bond
forming reaction, such as a catalytic asymmetric aldol reaction
with an unmodified ester as a donor, has been launched in our
laboratory.
6 Conclusions
We have developed a novel linked-BINOL as an approach
towards practical asymmetric catalysis. The linked-BINOL
efficiently stabilized the heterobimetallic multifunctional
asymmetric catalyst, Ga-Li complex, against ligand exchange
with the nucleophile, thus greatly improving the chemical yield
in the epoxide opening reaction. Further application of linked-
BINOL to La metal led to an air-stable, storable, and reusable
Figure 13. Working model for transition state.
monometallic multifunctional asymmetric catalyst, La-linked-
[55]
BINOL,
for the Michael reaction. Finally, the homobime-
As mentioned previously, the usefulness of the aldol adducts
increases if the 2-methoxyphenyl moiety functions as a
placeholder for further conversions. As shown in Scheme 6,
the BaeyerÀ Villiger oxidation proceeded smoothly by treat-
ing the ketones 49a and 50a with mCPBA, probably with the
aid of neighboring oxygen atoms. Interestingly, benzoate 51a
was obtained in 89% yield when acetonide 49a was used. On
the other hand, phenyl ester 52a was obtained in 93% yield
when a carbonate analogue 50a was subjected to the same
conditions. No regioisomer was observed in either case.
Furthermore, 50a afforded amide 53a exclusively in 97% yield
in one step via the Beckmann rearrangement with O-mesity-
lenesulfonylhydroxylamine (MSH).[53] The amide 53a was
readily transformed into 54a by reduction with DIBAL; 54a
can be converted into an amino-diol after oxidative removal of
the 2-methoxyphenyl group.[54]
tallic multifunctional asymmetric catalysis was realized by
utilizing the unique property of linked-BINOL. An Zn-Zn-
linked-BINOL complex provided a practical process for the
synthesis of syn-1,2-diols. We believe that the successful
development and applications of linked-BINOL has opened
up a new possibility of multifunctional asymmetric catalysis
towards practical catalytic asymmetric processes. However, it
is obvious that further intensive investigations based on novel
and more sophisticated concepts are still required to develop
really practical, especially environmentally benign, processes.
Our research projects on multifunctional asymmetric catalysis
are ongoing towards this goal.
Acknowledgements
A new homobimetallic multifunctional asymmetric catalysis
was achieved using linked-BINOL 10.[50,52] The results suggest
a novel use for linked-BINOL in addition to stabilization of
The research in this review was realized through creative and enthusiastic
work by coworkers, whose names are acknowledged in the publications from
our laboratory cited in this paper.
O
OMe
OMe
O
O
O
O
O
O
References and Notes
(i)
Ph
Ph
Ph
O
Baeyer−Villiger
oxidation
49a
51a
89%
[1] R. Noyori, Asymmetric Catalysis in Organic Synthesis, Wiley, New
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O
O
OMe
O
O
O
O
(i)
O
Ph
52a
Baeyer−Villiger
oxidation
50a
O
OMe
93%
Beckmann
rearrangement
(ii)
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97%
O
OH
OMe
O
O
H
(iii)
N
Ph
54a
N
Ph
H
53a
OH
94%
OMe
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O
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(i) mCPBA, NaH2PO4, ClCH2CH2Cl, 50 °C, 2h
(ii) O-mesitylenesulfonylhydroxylamine, CH2Cl2, rt, 4 h
(iii) DIBAL, −78 °C to rt, 2 h.
Scheme 6. Transformations of aldol adducts via regioselective
rearrangement.
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Adv. Synth. Catal. 2002, 344, 3 15
13

Shigeki Matsunaga et al.
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14
Adv. Synth. Catal. 2002, 344, 3 15

Linked-BINOL: An Approach towards Practical Asymmetric Multifunctional Catalysis
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Adv. Synth. Catal. 2002, 344, 3 15
15