Non-C2-symmetric, chirally economical, and readily tunable linked-binols: Design and application in a direct catalytic asymmetric mannich-type reaction

Article abstract of DOI:10.1002/anie.200500425

(Chemical Equation Presented) An achiral unit is shown to be better than a chiral unit in promoting an asymmetric reaction. Non-C₂-symmetric linked-binols 1 with one chiral 1,1′-bi-2-naphthol unit and one flexible achiral unit are employed as l

Full text of DOI:10.1002/anie.200500425

Communications
Asymmetric Catalysis
Non-C2-Symmetric, Chirally Economical, and
Readily Tunable Linked-binols: Design and
Application in a Direct Catalytic Asymmetric
Mannich-Type Reaction**
Takamasa Yoshida, Hiroyuki Morimoto,
Naoya Kumagai, Shigeki Matsunaga,* and
Masakatsu Shibasaki*
Asymmetric catalysis employing chiral metal complexes is
one of the most general and flexible methods in asymmetric
synthesis.[1] In the development of asymmetric metal catalysts
for highly enantioselective and reactive reactions, the design
of chiral ligands for the metal center is of key importance: the
activity and selectivity of the metal centers can be tuned by
chiral ligands. A delicate balance between the steric and
electronic properties of the catalyst determines the reaction
efficiency. Thus, a chiral ligand with a readily tuneable
framework is desirable.[2]
We recently reported the preparation of a series of chiral
ligands termed “linked-binols” (1a–c; Scheme 1).[3,4] These
linked-binols consist of two chiral 1,1’-bi-2-naphthol units
connected at the 3 and 3’’-positions by a flexible linker
containing one heteroatom. Linked-binols often provide a
better chiral environment than 1,1’-bi-2-naphthol (2;
[*] T. Yoshida, H. Morimoto, N. Kumagai, Dr. S. Matsunaga,
Prof. Dr. M. Shibasaki
Graduate School of Pharmaceutical Sciences
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax: (+81)3-5684-5206
E-mail: smatsuna@mol.f.u-tokyo.ac.jp
mshibasa@mol.f.u-tokyo.ac.jp
[**] This work was supported by a Grant-in-Aid for Specially Promoted
Research and a Grant-in-Aid for Encouragements for Young
Scientists (B) (for S.M.) from JSPS and MEXT.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200500425
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Scheme 2. Structure of a Zn/1a (3:2) complex.
Scheme 1. Structures of (S,S)-linked-binols 1a–c, 1,1’-bi-2-naphthol 2,
and new ligands 3.
Scheme 1), as was demonstrated in various catalytic asym-
metric reactions, such as epoxide openings,[3a] a direct aldol
reaction,[5] Michael reactions,[6,7] and direct Mannich-type
reactions.[8] Although they are conformationally rigid, two
chiral binaphthyl units seem essential to provide an efficient
chiral environment for high enantioselectivity; however, they
also impose severe limitations on ligand design. So far, the
properties of linked-binol complexes could only be tuned by
changing the heteroatom of the linker (1a–c).[3] Electronic
and steric modifications of the binaphthyl moiety is tedious
and lengthy because of the presence of two chiral units. Thus,
improving the performance of ligands with the original
linked-binol framework in catalytic reactions is a formidable
challenge. For example, many steps are required when
modifying the electronic properties by preparing 6,6’,6’’,6’’’-
tetrasubstituted C2-symmetric linked-binols. A simple, more
flexible strategy is required to overcome this intrinsic
dilemma and tune the properties of linked-binols. Herein,
we report a readily tuneable, non-C2-symmetric linked-binol 3
with only one chiral 1,1’-bi-2-naphthol unit and one flexible
achiral unit (Scheme 1).[9] On the basis of our mechanistic
studies on the Et2Zn/linked-binol 1a catalytic system, new
ligands were designed and evaluated in direct catalytic
asymmetric Mannich-type reactions. The introduction of an
achiral unit was not only economical in terms of chirality[10]
but also afforded comparable enantioselectivity and a much
higher reaction rate than the original linked-binol 1a with two
chiral 1,1’-bi-2-naphthol units.
For the design and evaluation of the new linked-binols, a
Et2Zn/1a complex was used for reference because its
structure and reactivity had been previously studied. The
structure of the Zn/1a (3:2) precatalyst, prepared from Et2Zn/
1a (2:1; Scheme 2), was determined by X-ray crystallo-
graphic, NMR spectroscopic, and ESI mass-spectrometric
analysis.[11] In the Zn/1a (3:2) complex, neither of the linked-
binol units had a C2-symmetric environment and one of the
phenolic OH groups remained unchanged, even in the
presence of a slight excess of Et2Zn. On the other hand,
there was a linear relationship between the enantiomeric
excess of product 6a and that of the chiral ligand 1a used in
the Mannich-type reaction of diphenylphosphanoylimine
(4a) and hydroxyketone 5 (Figure 1).[12] The structure of the
Figure 1. Linear relationship between Mannich-adduct 6a and (S,S)-
linked-binol 1a observed in a direct Mannich-type reaction of 4a with
5.
Zn/1a (3:2) complex (Scheme 2) and the results shown in
Figure 1 suggested that 1) C2 symmetry in linked-binol 1a is
not important, 2) one phenolic OH group is not required, and
3) a homochiral complex is more favorable than a hetero-
chiral complex. We hypothesized that one of the chiral
binaphthol units could be replaced with an achiral unit, such
as an atropisomeric biphenol or an achiral phenol derivative.
Chirality should be then transferred to the flexible achiral unit
on complexation with a zinc center, and a similar chiral
environment should be obtained with a ligand that was
economical in terms of chirality.
The structures of ligands 3a–k are shown in Scheme 3.[13]
The catalytic potential of these ligands was evaluated in a
direct asymmetric Mannich-type reaction of imine 4a and
hydroxyketone 5 using 5 mol% of ligand 3 and 20 mol% of
Et2Zn at À208C in THF/CH2Cl2 ([imine] = 150 mm, [3] =
7.5 mm). When the original ligand 1a was used, the reaction
was completed within 1 h and the Mannich adduct 6a was
obtained in 99% yield with anti/syn selectivity of 98:2 in
> 99% ee (Table 1, entry 1). A control experiment with
10 mol% of binol 2 had a much lower reaction rate and
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Scheme 3. Structures of non-C2-symmetric (S)-linked-binol derivatives 3a–k containing one achiral unit and one chiral binaphthol unit.
were readily accessible from commercially available salicylic
aldehyde derivatives.[15]
Table 1: Catalytic asymmetric Mannich-type reaction using various chiral
ligands (1a, 2, and 3a–k).
Although many ligands in Scheme 3 gave high enantiose-
lectivities (Table 1), it was difficult to compare their perfor-
mance precisely in terms of reaction rate. Generally, catalyst
concentration becomes rather low when catalyst loading is
reduced to < 0.1 mol% because of substrate-solubility lim-
itations. Thus, high turnover frequencies (TOF) and turnover
numbers (TON) under dilute conditions are required to lower
the catalyst loading. To evaluate the ligands quantitatively,
the reaction for each ligand was monitored under dilute
conditions ([imine] = 31 mm, [3] = 0.31 mm, 1 mol%; Table 2
Entry
Ligand
(mol%)
[Ligand]
[mm]
t [h]
Yield [%]
anti/syn
ee [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
1a (5)
2 (10)
3a (5)
3b (5)
3c (5)
3d (5)
3e (5)
3 f (5)
3g (5)
3h (5)
3i (5)
3j (5)
3k (5)
7.5
15
1
68
1
1
1
23
11
5
1
1
99
85
99
98
99
74
92
93
98
95
94
96
95
97:3
87:13
94:6
98:2
97:3
91:9
95:5
95:5
96:4
98:2
98:2
98:2
98:2
>99
24
99
98
99
9
90
87
99
98
98
98
98
7.5
7.5
7.5
7.5
7.5
7.5
7.5
7.5
7.5
7.5
7.5
Table 2: Initial reaction rate with various chiral ligands (1a, 2, and 3a–k)
under dilute conditions.
1
1
1
Entry
Ligand (mol%)
[Ligand] [mm]
Initial rate [mmminÀ1
]
1
2
3
4
5
6
7
8
9
10
11
12
13
1a (1)
2 (2)
0.31
0.62
0.31
0.31
0.31
0.31
0.31
0.31
0.31
0.31
0.31
0.31
0.31
0.199
0.015
0.333
0.354
0.696
0.019
0.096
0.135
0.375
0.455
0.435
0.742
0.848
3a (1)
3b (1)
3c (1)
3d (1)
3e (1)
3 f (1)
3g (1)
3h (1)
3i (1)
3j (1)
3k (1)
ee value (68 h, 24% ee; entry 2). Ligand 3a, which lacks one
phenolic OH group, gave results similar to those obtained
with 1a (entry 3). Ligand 3b with an atropisomeric biphenol
unit was also efficient (entry 4), thus suggesting that the
chirality of the biphenol unit was controlled by complexation
with the zinc center.[14] Even an achiral unit, such as 3c, gave
excellent results (1 h, 99% yield, 99% ee; entry 5), whereas
ligand 3d, which has a phenolic OH group in the 2’-position,
had a low reaction rate and poor enantioselectivity (23 h,
74% yield, 9% ee; entry 6). Ligands 3e and 3 f also produced
unsatisfactory yields and modest enantioselectivities
(entries 7 and 8). The results shown in entries 5–8 imply that
both the phenolic OH group at the proper position and a
substituent on the aromatic ring are required. To evaluate the
effects of substituents on the phenol ring, ligands 3g–k were
used, and all of them showed a high reactivity and enantio-
selectivity (entries 9–15). The achiral units in ligands 3i–k
and Figure 2). The initial rate of the reaction with each ligand
(1a, 2, and 3a–k) is summarized in Table 2, and the profiles of
the reactions with ligands 1a, 2, 3c, 3j, and 3k are shown in
Figure 2.[16] It is of note that many ligands with achiral units
(shown in Scheme 3) gave a better reaction rate than the
original linked-binol 1a that contained two chiral units (initial
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Scheme 5. Catalytic asymmetric Mannich-type reaction of imines 4a–d
using 3c.
mixture was difficult for both 1a and 3c. Thus, we investigated
the structures of precatalysts of a Et2Zn/ligand mixture in a
2:1 ratio for a preliminary evaluation of the properties of 3c
relative to 1a.[19] The complex formed in the Et2Zn/3c (2:1)
mixture was confirmed to be similar to that in the Et2Zn/1a
(2:1) mixture (Zn/1a = 3:2; Scheme 2) by ESI mass-spectro-
metric analysis. The ESIMS spectrum of the Et2Zn/3c (2:1)
mixture showed major peaks at m/z 1183–1194,[20] which
~
Figure 2. Reaction profiles with chiral ligands: 1a ( =0.31 mm), 2
&
*
(
(
=0.62 mm), 3c ( =0.31 mm), 3j (ꢀ=0.31 mm), and 3k
=0.31 mm).
*
1
correspond to a Zn/3c (3:2) complex. The H and 13C NMR
rate = 0.199 mm minÀ1). Ligands 3j and 3k with electron-
donating tBu groups gave the highest reaction rates (3j =
0.742 mm minÀ1, 3k = 0.848 mm minÀ1), and ligand 3c also
produced a comparable reaction rate (3c = 0.696 mm minÀ1).
Ligand 3g, with a bulky aromatic substituent, had lower
reactivity than 3c but higher reactivity than 1a. An electron-
withdrawing group also had a lower reaction rate (3h and 3i).
These results suggested that an appropriate group at the
ortho position of the phenolic OH group and a relatively less
acidic phenolic OH group were suitable substituents on the
ligands for the present Mannich-type reaction. These results
demonstrated the usefulness of the present strategy to
sterically and electronically fine-tune complexes of metal
and linked-binols.
spectroscopic analysis of the Et2Zn/3c (2:1) mixture indicated
eight different benzylic protons and four benzylic carbon
atoms,[20] thus suggesting that the Zn/3c (3:2) complex does
not have C2 symmetry, and that two molecules of 3c were
differentially involved, possibly in a head-to-tail fashion.
Further investigations to determine the structure of the Zn/3c
complex unequivocally are ongoing. Although the structure
of the actual active species formed under the reaction
conditions is not clear at the moment, we speculate that the
coordination site at the zinc center would be sterically less
crowded in the Zn/3c complex than in the Zn/1a complex,
thus accelerating the rate-limiting exchange step[21] between
the product and ketone 5 to regenerate the Zn/ligand/ketone
complex. Further mechanistic studies are in progress.
The utility of ligand 3c was further demonstrated, as
shown in Schemes 4 and 5. The catalyst loading for 3c was
successfully lowered: the Mannich-type reaction proceeded
smoothly with as little as 0.01 mol% of 3c, with the product
being afforded in good yield and selectivity at 08C after 36 h
(86%, 98% ee, TON = 8600; this is the highest TON value
achieved in the catalytic asymmetric Mannich-type reaction
so far.[17,18]) The reaction proceeded smoothly even with low
concentrations of the ligand ([3c] = 0.095 mm). The broad
substrate range of ligand 3c is also summarized in Scheme 5.
Although a Et2Zn/ligand stoichiometry of 4:1 was used for
the Mannich-type reaction, characterization of the reaction
In summary, we have developed readily tuneable, eco-
nomical in terms of chirality, non-C2-symmetric linked-binol
derivatives. The new design overcomes the drawbacks
inherent in the original C2-symmetric ligand 1a with two
chiral binaphthol units. The present strategy has been useful
to fine-tune metal/linked-binol complexes in a direct catalytic
asymmetric Mannich-type reaction. Further application of
these new sterically and electronically tuneable ligands to
other asymmetric reactions, in which the original linked-binol
1a produced unsatisfactory results, is currently ongoing.
Received: February 4, 2005
Published online: April 28, 2005
Keywords: amino alcohols · asymmetric catalysis ·
.
chiral ligands · Mannich reaction · zinc
[1] For general reviews, see: a) Comprehensive Asymmetric Catal-
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Scheme 4. Catalytic asymmetric Mannich-type reaction using
0.01 mol% of 3c. MS 3 ꢁ=molecular sieves (3 ꢁ).
[2] For recent reviews on asymmetric catalysis using sterically and
electronically modified binol derivatives, see: a) Y. Chen, S.
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Yekta, A. K. Yudin, Chem. Rev. 2003, 103, 3155; b) P. Kocovsky,
meso-linked-binol. The chirality of ligand 3b should be con-
trolled by (S)-biphenol-(S)-binol on complexation with the zinc
center because the pseudo-meso-(R)-biphenol-(S)-binol-type
complex would afford products in low enantiomeric excess.
[15] In terms of cost efficiency, 3b and 3c are also superior to 1a: 2,2’-
biphenol (500 g; Aldrich) and 2-phenylphenol (500 g; Aldrich).
[16] The reaction profiles with other ligands are summarized in the
Supporting Information.
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sulfur-linked-binol 1b, see: c) N. Kumagai, S. Matsunaga, T.
Kinoshita, S. Harada, S. Okada, S. Sakamoto, K. Yamaguchi, M.
Shibasaki, J. Am. Chem. Soc. 2003, 125, 2169; for the nitrogen-
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Ohshima, M. Shibasaki, J. Am. Chem. Soc. 2003, 125, 15837.
[4] For the design and application of related chiral ligands, see:
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Tetrahedron Lett. 1998, 39, 7917; b) H. Ishitani, T. Kitazawa, S.
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[17] For reviews of catalytic asymmetric Mannich-type reactions, see:
a) S. Kobayashi, M. Ueno in Comprehensive Asymmetric
Catalysis Supplement I (Eds.: E. N. Jacobsen, A. Pfaltz, H.
Yamamoto), Springer, Berlin, 2003, chap. 29.5, p. 143; b) A.
Cꢀrdova, Acc. Chem. Res. 2004, 37, 102; for selected recent
examples of direct catalytic asymmetric Mannich(-type) reac-
tions, see also; c) B. List, P. Pojarliev, W. T. Biller, H. J. Martin, J.
Am. Chem. Soc. 2002, 124, 827; d) A. Cꢀrdova, W. Notz, G.
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M. Terada, J. Am. Chem. Soc. 2004, 126, 5356, and references
therein.
[7] Y. S. Kim, S. Matsunaga, J. Das, A. Sekine, T. Ohshima, M.
Shibasaki, J. Am. Chem. Soc. 2000, 122, 6506; see also Ref. [3d]
[8] a) S. Matsunaga, N. Kumagai, S. Harada, M. Shibasaki, J. Am.
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[18] The best TON was achieved using 0.02 mol% of 1a ([ligand
1a] = 0.21 mm, TON = 4900)[8b]; however, the concentration of
1a had to be > 0.2 mm to promote the reaction efficiently.
Under similar conditions given in Scheme 2 ([ligand 1a] =
0.1 mm, 0.01 mol%), TON < 4000.
[19] In the present Mannich-type reaction, the ratio of Et2Zn/ligand
(1a or 3c) did not affect enantioselectivity. Et2Zn/1a (2 mol% of
1a): 2:1 (> 99% ee, d.r. 98:2, 2 h, > 95% yield), 3:1 (> 99% ee,
d.r. 98:2, 1 h, > 95% yield), 4:1 (> 99% ee, d.r. 98:2, 1 h, > 95%
yield); Et2Zn/3c (2 mol% of 3c): 2:1 (99% ee, d.r. 99:1, 1 h,
> 95% yield), 3:1 (98% ee, d.r. 98:2, 1 h, > 95% yield), 4:1
(98% ee, d.r. 98:2, 1 h, > 95% yield); thus, we assumed that a
similar active species formed under these reaction conditions,
and that the structural information obtained with Et2Zn/ligand
(2:1) would give some insight into the properties of 3c.
[20] ESI mass spectra as well as the 1H NMR and 13C NMR spectra of
Et2Zn/3c (2:1) are given in the Supporting Information. The ESI
mass-spectrometric analysis showed several signals that corre-
spond to the Zn/3c (3:2) trinuclear complex, depending on the
natural-isotope distribution pattern of zinc.
[9] For selected, recent, related examples using a conformationally
flexible biphenyl unit in asymmetric catalysis, see: a) K. Mikami,
T. Korenaga, M. Terada, T. Ohkuma, T. Pham, R. Noyori,
Angew. Chem. 1999, 111, 517; Angew. Chem. Int. Ed. 1999, 38,
495; b) J. Balsells, P. J. Walsh, J. Am. Chem. Soc. 2000, 122, 1802;
c) T. Ooi, Y. Uematsu, M. Kameda, K. Maruoka, Angew. Chem.
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114, 4714; Angew. Chem. Int. Ed. 2002, 41, 4532; for other
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2003, 103, 3297; g) J. W. Faller, A. R. Lavoie, J. Parr, Chem. Rev.
2003, 103, 3345; h) A. Alexakis, C. Benhaim, Eur. J. Org. Chem.
2002, 3221.
[10] For “chiral economy” in total synthesis, see: A. Fischli, Chimia
1976, 30, 4; for “chirality economy” in asymmetric catalysis, see
Ref. [9e]
[21] The rate-limiting step of the Mannich-type reaction of 4a with 5
was determined to be a catalyst-turnover step by kinetic studies
on the initial rate; see Ref. [8b]
[11] For characterization of the Zn/linked-binol 1a (3:2) complex,
see Ref. [3c]: mechanistic studies conducted therein reported that
the actual active species was supposed to have
a more
complicated structure that incorporated hydroxy ketone 5;
ESI-mass-spectrometric analysis revealed that a Zn/linked-
binol/ketone 5 (7:3:4) complex could be an active species
under the reaction conditions.
[12] For reviews on nonlinear effects, see: a) C. Girard, H. B. Kagan,
Angew. Chem. 1998, 110, 3088; Angew. Chem. Int. Ed. 1998, 37,
2922; b) H. B. Kagan, Adv. Synth. Catal. 2001, 343, 227; c) D. G.
Blackmond, Acc. Chem. Res. 2000, 33, 402.
[13] For the synthesis and spectra of ligands 3a–k, see the Supporting
Information.
[14] The initial reaction rate of the Mannich-type reaction with a
meso-linked-binol derivative prepared from (S)-binol and (R)-
binol units was estimated relative to that of (S,S)-linked-binol
1a. A similar initial reaction rate was observed for 1a and the
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