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Synthesis 2013; 45(4): 421-437
DOI: 10.1055/s-0032-1316846
review
© Georg Thieme Verlag Stuttgart · New York

Multimetallic Schiff Base Complexes as Cooperative Asymmetric Catalysts

Shigeki Matsunaga*
a   Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan   Fax: +81(3)56845206   Email: smatsuna@mol.f.u-tokyo.ac.jp
b   Japan Science and Technology Agency, ACT-C, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
,
Masakatsu Shibasaki*
c   Institute of Microbial Chemistry, Kamiosaki 3-14-23, Shinagawa-ku, Tokyo 141-0021, Japan   Email: mshibasa@bikaken.or.jp
› Author Affiliations
Further Information

Publication History

Received: 30 November 2012

Accepted after revision: 19 December 2012

Publication Date:
14 January 2013 (online)

 
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Abstract

Multimetallic salen and related Schiff base complexes designed for cooperative asymmetric catalysis are introduced. First, studies to enhance the cooperative function of two distinct metal–salen units using covalently linked metal–salen complexes, supramolecular bimetallic salens as well as μ-oxo-bridged metal salens are described. Then, studies to design dinuclear Schiff base catalysts that exhibit unique intramolecular cooperative functions of two distinct metals are discussed in detail.

1 Introduction

2 Covalently Linked Metal Salens

3 Supramolecular Bimetallic Salens

4 μ-Oxo-Bridged Metal Salens

5 Heterodinuclear Schiff Base Complexes

6 Homodinuclear Schiff Base Complexes

7 Summary


#

Key words

asymmetric catalysis - asymmetric synthesis - bifunctional catalysis - cooperative catalysis - Schiff bases - salen

Biographical Sketches

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Shigeki Matsunaga is an associate professor at the University of Tokyo. He was born in 1975 in Kyoto, and received his Ph.D. from the University of Tokyo under the direction of Professor Masakatsu Shibasaki. He started his academic career in 2001 as an assistant professor in Professor ­Shibasaki’s lab at the University of Tokyo. He was promoted to a senior lecturer in 2008, and to his current position in 2011. He is the recipient of several awards, including the Chemical Society of Japan Award for Young Chemists (2006), the Mitsui Chemicals Catalysis Award of Encouragement (2009), and the Merck-Banyu Lectureship Award 2010. His research interests are in cooperative catalysis, asymmetric catalysis, and design and synthesis of biologically active compounds.

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Masakatsu Shibasaki received his Ph.D. from the University of Tokyo in 1974 with Professor Shun-ichi Yamada before his post-doctoral studies with Professor E. J. Corey (Harvard University). In 1977, he joined Teikyo University as an associate professor. In 1983, he moved to Sagami Chemical Research Center as a group leader, and in 1986 took up a professorship at Hokkaido University, before returning to the University of Tokyo as a professor in 1991. Currently, he is a director of the ­Institute of Microbial Chemistry (Tokyo). His research interests include asymmetric catalysis and medicinal chemistry of biologically significant compounds.

1

Introduction

The usefulness of asymmetric catalysis for the efficient synthesis of enantiomerically enriched compounds has been established.[ 1 ] Catalytic asymmetric processes are potentially more economical and environmentally benign over those using stoichiometric amounts of chiral reagents. The development of asymmetric catalysts that exhibit high activity, high stereoselectivity, and broad substrate generality in a step- and atom-economical manner is a major theme in modern organic synthesis. To address this issue, the concept of cooperative catalysis is often utilized for the design of both metallic catalysts and organocatalysts,[ 2 ] wherein both partners of a bimolecular reaction are simultaneously activated (dual activation, see Figure [1]) with fine-tuned asymmetric catalysts. The dual-activation mechanism often leads to higher reaction rate under mild reaction conditions, better stereoselectivity, and broader substrate generality than a conventional mono-activation mechanism, such as chiral Lewis acid catalysis.

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Figure 1 Dual activation with bimetallic cooperative asymmetric catalysts

When designing cooperative asymmetric catalysts, the construction of a suitable chiral environment for each targeted reaction is important for achieving efficient dual activation of nucleophiles and electrophiles. Various chiral scaffolds have been utilized to realize efficient cooperative dual activation. Among them, metal–salen and related Schiff base complexes are widely used as privileged catalysts,[3] [4] and various types of cooperative asymmetric catalysts based on salen scaffolds have been reported. In this review article, multimetallic salen and Schiff base complexes that exhibit an intramolecular cooperative function, leading to highly enantioselective and synthetically useful transformations, are highlighted. The focus is placed on multimetallic Schiff base complexes in which both nucleophiles and electrophiles are activated by distinct nuclei of the same metal complex. Intermolecular cooperative bimolecular catalysis with mononuclear metal–salen complexes,[ 5 ] other aspects of metal–salen complexes[ 6 ] including polymer-supported variants,[ 7 ] and other multimetallic asymmetric catalysts with different chiral scaffolds[ 8 ] are not discussed in this review.


# 2

Covalently Linked Metal Salens

Mononuclear metal–salen catalysts have been widely utilized in various enantioselective transformations during the last two decades.[3] [5] As a part of mechanistic studies on the metal–salen catalysis, Jacobsen and co-workers revealed that some mononuclear metal–salen complexes (M-L1), such as Cr–salen,[ 9 ] Co–salen,[ 10 ] and Al–salen complexes,[ 11 ] showed a second-order rate-dependence on the concentration of catalysts. The second-order dependence indicated an intermolecular bimolecular cooperative mechanism of those metal–salen catalysts.[ 12 ] The postulated bimolecular cooperative mechanism of two Cr-L1 complexes in the asymmetric ring opening of meso epoxides is shown in Scheme [1]. One Cr-L1 complex acts as a Lewis acid to activate electrophiles, while the other generates nucleophilic species. By placing two metal-salen units in close proximity with an appropriate relative orientation, more efficient intramolecular cooperative function of two metal–salen units can be expected. Jacobsen and co-workers systematically studied the position and length of covalent linkers to connect two Cr-L1 units. A covalently linked dimeric Cr-salen catalyst shown in Figure [2] was the best, and was favorable for promoting the asymmetric ring-opening reaction of epoxides with azide via head-to-tail geometry in the transition state. The length of the linker was also important and mainly affected the reaction rate. The C5-linker (n = 5) maximized the intramolecular cooperative pathway in comparison with the intermolecular cooperative pathway.[ 13 ] With the optimized covalently linked dimeric catalyst, the reaction rate was improved by two orders of magnitude, while maintaining comparable enantioselectivity (93% ee).

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Scheme 1 Postulated bimolecular cooperative mechanism of two Cr-L1 complexes
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Figure 2 Covalently linked dimeric Cr-salen, Al-salen, and Co-salen complexes

A covalently linked dimeric Al-salen catalyst with the same spacer shown in Figure [2] was also effective at improving the catalytic activity of a corresponding mononuclear Al-salen complex. In the asymmetric 1,4-addition of cyanide to α,β-unsaturated imides, the mononuclear Al-L1 complex alone afforded good enantioselectivity, but there remained much room for improvement in terms of the catalyst reactivity.[ 14 ] The covalently linked Al-salen complexes (n = 5, 6, 7) improved the reactivity by several orders of magnitude. In addition, the dimeric Al-salen catalysts showed good functional group compatibility. Just 5 mol% catalyst (based on the Al-salen unit) smoothly promoted the reaction of various β-alkyl α,β-unsaturated imides with cyanide, giving products in yields ranging from 91 to >99% and enantiomeric excess values from 84 to 96% (Scheme [2]).[ 15 ]

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Scheme 2 Catalytic asymmetric 1,4-addition of cyanide to β-alkyl α,β-unsaturated imides with covalently linked dimeric Al-salen complex

Because the mononuclear Co-L1 complex catalyzes the hydrolytic kinetic resolution of racemic epoxides with an excellent selectivity factor and provides versatile chiral terminal epoxides in excellent enantiopurity,[ 10 ] attempts to improve catalytic performance of the Co-L1 complex by covalently linking two Co-salen units have been undertaken by many researchers,[ 16 ] with methods including immobilization onto polymers,[ 17 ] dendrimers,[ 18 ] and gold colloids.[ 19 ] In many cases, significant rate acceleration was observed while maintaining the high enantio-discriminating ability of the Co-salen unit.

From among many studies, it was found that some dimeric and oligomeric Co-salen complexes not only enhance the reaction rate of the hydrolytic kinetic resolution, but also broaden the reaction scope of the Co-salen catalysis. The advantage of the dimeric Co-salen catalyst in Figure [2] (n = 6) was clearly observed in the desymmetrization of meso epoxy alcohols via intramolecular cyclization (Scheme [3]). The covalently linked dimeric Co-salen catalyst (2 mol% based on Co amount) gave product in quantitative yield and 84% ee,[ 20 ] while the original monomeric Co-L1 complex resulted in only 22% yield and 60% ee.

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Scheme 3 Catalytic asymmetric intramolecular cyclization of meso epoxy alcohol

The utility of oligomeric Co-salen catalysts was also demonstrated by Jacobsen and co-workers in the enantioselective hydrolysis of cyclohexene oxide. The oligomeric Co(OTs)-salen catalyst in Scheme [4] gave cyclohexane-1,2-diol in 98% yield and 94% ee, while the parent monomeric Co-L1 catalyst resulted in modest reactivity and enantioselectivity.[ 21 ] After further optimization of the linker structure as well as the synthetic procedure, the same research group achieved a chromatography-free concise synthesis of a highly active oligomeric Co(NBS)-salen catalyst (NBS = 3-nitrobenzenesulfonate) in >95% yield (3 steps, Scheme [5], eq A).[ 22 ] As little as 0.0004 mol% of the oligomeric Co(NBS) catalyst was sufficient to promote the hydrolytic kinetic resolution of terminal epoxides, giving enantiomerically enriched terminal epoxides and 1,2-diols (Scheme [5], eq B). The same catalyst also showed superior activity in the kinetic resolution of terminal epoxides with alcohols and phenols, giving products in 99% ee (Scheme [5], eqs C and D). Weck and co-workers also reported the related oligomeric Co-salen complexes prepared via ruthenium-catalyzed olefin metathesis.[ 23 ]

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Scheme 4 Oligomeric Co-salen catalyst for hydrolytic desymmetrization of a meso epoxide
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Scheme 5 Chromatography-free synthesis of an oligomeric Co(NBS)-salen catalyst and its application to the kinetic resolution of terminal epoxides

Jacobsen and co-workers also utilized the related oligomeric Co(OTf)-salen complex in the desymmetrization of meso oxetanes via asymmetric intramolecular ring-opening reactions with oxygen nucleophiles (Scheme [6]).[ 24 ] The oligomeric Co-salen catalyst showed higher reactivity than the monomeric Co-L1 complex by two orders of magnitude. Intramolecular ring opening of oxetanes with alcohol and phenol units proceeded nicely, and 0.01 mol% of the oligomeric Co(OTf)-salen catalyst gave products in high enantioselectivity (88–99% ee). There remained room for improvement, however, when using an oxetane bearing a nitrogen nucleophile.

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Scheme 6 Desymmetrization of meso oxetanes using an oligomeric Co-salen catalyst

Coates and co-workers developed a bimetallic Co-salen catalyst linked through a 1,1′-bi-2-naphthol framework[ 25 ] for enantioselective polymerization of epoxides. The bimetallic R,R,S,R,R-configured catalyst selectively polymerized the S-epoxide, and the R-epoxide was recovered in high enantiopurity (Scheme [7], eq A). When using a racemic catalyst (i.e., an equimolar mixture of R,R,S,R,R- and S,S,R,S,S-configured catalysts), isoselective polymerization of racemic epoxides proceeded, and highly isotactic polyethers were obtained in >99% yield (Scheme [7], eq B). Molecular modeling suggested that the distance between the two cobalt centers can readily span the desirable range of 5–7 Å as the bimetallic complex pivots about the CNap–CNap bond. Two chiral Co-salen units are thus in suitable positions to work cooperatively by a mechanism similar to that observed in related epoxide-ring-opening reactions.

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Scheme 7 Catalytic, highly isotactic polymerization of terminal epoxides promoted by a bimetallic Co-salen catalyst

# 3

Supramolecular Bimetallic Salens

In addition to covalently linking two metal-salen units, there are several reports of placing the two units in close proximity using supramolecular interactions. Mirkin and co-workers demonstrated the linkage of two Cr-salen complexes via two Rh-phosphine units bearing a coordinative thioether moiety.[ 26 ] The supramolecular Cr-salen/Rh-phosphine complexes were utilized for the ring-opening reaction of an epoxide with azide. The distance between two Cr-salen units was reversibly switched by changing the coordination mode of the rhodium centers (Scheme [8], closed form and open form). As expected, the reactivity of the supramolecular catalyst changed depending on the rhodium coordination mode, and much higher reaction rate was observed with the closed form. The enantioselectivity obtained with the supramolecular Cr-salen catalyst in Scheme [8] was, however, only moderate, possibly due to unfavorable orientation of two Cr-salen units to induce good selectivity.

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Scheme 8 Supramolecular linkage of two Cr-salen units

Hong and co-workers utilized hydrogen-bonding interactions to form self-assembled homodimeric Co-salen complexes.[27] [28] [29] Depending on the targeted reaction, hydrogen-bonding units were modified to properly adjust the distance between two Co-salen units. For the catalytic asymmetric Henry reaction of aryl aldehydes with nitromethane, the self-assembled complex shown in Scheme [9] was utilized as the first-generation catalyst, and products were obtained in 81–96% ee.[ 27 ] Importantly, high enantio­selectivity and reactivity were realized only when using the supramolecular complex. The simple mononuclear CoII-L1 complex resulted in poor yield (11%) and moderate enantioselectivity (55% ee). After further optimization of the self-assembly mode as well as a counter-ion of cobalt(III), the second-generation cobalt(III) catalyst based on the urea hydrogen-bonding pattern was developed (Scheme [10]). With the second-generation self-assembled catalyst, not only enantioselectivity but also the substrate generality of the Henry reaction was drastically improved (Scheme [10], eq A; 91–97% ee, R = aryl, alkyl, and alkenyl). Hong and co-workers further expanded the synthetic utility of the homodimer to the anti-selective catalytic asymmetric Henry reaction, and products were obtained in 85–99% ee and anti-selectivity ranging from >50:1 to 1.1:1 (Scheme [10], eq B).[ 28 ] The self-assembled homodimer with urea hydrogen-bonding was also successfully utilized in the hydrolytic kinetic resolution of terminal epoxides. Significant rate acceleration was observed with the supramolecular system, and as little as 0.03 mol% of catalyst gave epoxides in 99% ee with 41–43% recovery yield under solvent-free conditions after 8–14 hours (Scheme [11]).[ 29 ] The urea units as well as the counter-ion of cobalt(III) were finely tuned depending on the reaction as illustrated in Schemes 10 and 11.

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Scheme 9 Catalytic asymmetric Henry reaction with the first-­generation self-assembled dimeric CoII-salen catalyst
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Scheme 10 The second-generation self-assembled dimeric CoIII-salen catalyst, using hydrogen-bonding at the urea moieties, for ­enantio- and diastereoselective Henry reaction
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Scheme 11 Hydrolytic kinetic resolution of racemic terminal epoxides with the self-assembled CoIII(OTs)-salen catalyst

# 4

μ-Oxo-Bridged Metal Salens

Metal–salen complexes often exist in a μ-oxo-bridged form, and μ-oxo-bridged metal–salen units are speculated to work cooperatively in some reactions. Belokon’, North, and co-workers utilized μ-oxo bridged Ti-L1 complexes for the catalytic asymmetric cyanation of aldehydes.[ 30 ] Good enantioselectivity (52–92% ee) was observed at room temperature with low catalyst loading (0.1 mol%, Scheme [12]). Based on mechanistic studies, μ-oxo-bridged dimeric Ti-L1 complexes are proposed as catalytically active species, while the monomeric oxo-Ti-L1 complex is inactive. A cooperative transition-state model was proposed, in which one Ti-L1 unit acts as a Lewis acid to activate aldehydes and the other Ti-L1 unit intramolecularly delivers cyanide. North and co-workers also utilized μ-oxo dimeric Al-L1 catalyst[31] [32] for cyanohydrin synthesis, in which a similar bimetallic cooperative mechanism was proposed.

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Scheme 12 Catalytic asymmetric cyanosilylation of aldehydes promoted by μ-oxo-bridged dimeric Ti-L1 complexes

In Belokon’s Ti-L1 system, the inactive monomeric oxo-Ti-L1 complex and catalytically active dimeric species were found to exist in equilibrium, dependent on the concentration. Ding and co-workers designed covalently linked μ-oxo-bridged dimeric Ti-salen complexes to suppress undesirable dissociation to the inactive oxo-Ti monomer. The linker of the Ti-salen units significantly affected enantioselectivity as well as catalytic activity. Flexible linkers used in Cr-salen, Al-salen and Co-salen systems (see Figure [2]) as well as some rigid linkers resulted in moderate reactivity and enantioselectivity. Both the length of the linker and the mutual orientation of two Ti-salen units were critical to enhance cooperative catalytic activity. After optimization studies, the dimeric Ti-salen catalyst shown in Scheme [13] was determined to be the best. The catalytic asymmetric cyanation of aldehydes proceeded with extremely low catalyst loading. As little as 0.0005–0.02 mol% of the bimetallic Ti-salen catalyst gave products in 87–99% yield and 64–97% ee (Scheme [13]).[ 33 ]

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Scheme 13 Covalently linked μ-oxo Ti-salen dimer for catalytic asymmetric cyanosilylation of aldehydes

Rajanbabu, Parquette, and co-workers reported the utility of a dimeric Y-L2 catalyst, derived from o-vanillin, for asymmetric ring opening of meso aziridines with azide and cyanide (Scheme [14]).[ 34 ] High enantioselectivity, up to 99% ee, can be ascribed to the well-organized dimeric structure, because a related monomeric Y-L2 complex prepared from Y[N(SiHMe2)2]3 resulted in modest enantio­selectivity. A cooperative mechanism, where one yttrium acts as a Lewis acid and the other delivers nucleophiles, is assumed. The same research group also utilized the dimeric Y-L2 catalyst for a regiodivergent ring-opening reaction of racemic terminal aziridines with azide.[ 35 ] As shown in Scheme [15], the dimeric Y-L2 catalyst promoted the ring opening reaction of alkyl-substituted racemic terminal aziridines with exceptionally high complementary regioselectivities; the nucleophilic addition of azide occurs at the terminal position for (R)-aziridines, while (S)-aziridines gave products resulting from SN2 inversion at the secondary position. Shibasaki, Matsunaga, and co-workers also demonstrated the utility of Schiff base L2 in combination with group II metals, such as dibutylmagnesium and strontium isopropoxide. The methoxy group in the Schiff base L2 was key to forming catalytically active oligomeric species. The structures of oligomeric group II metal–L2 complexes are, however, not clarified.[ 36 ]

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Scheme 14 Dimeric Y-L2 catalyst for asymmetric ring opening of meso aziridines with azide and cyanide
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Scheme 15 Dimeric Y-L2 catalyst for regiodivergent ring opening of racemic terminal aziridines with azide

Belokon’, North, Kagan and co-workers utilized a homodinuclear μ-oxo-bridged titanium–Schiff base catalyst for the asymmetric ring-opening reaction of meso epoxides with cyanide. The μ-oxo-bridged titanium catalyst was prepared from two molar equivalents of titanium isopropoxide and Schiff base L3 derived from a 1,1′-bi-2-naphthol derivative and amino alcohol units. The dinuclear Ti-L3 catalyst was applicable to five- to eight-membered-ring cyclic meso epoxides, giving products in 91–94% ee (Scheme [16]).[ 37 ] Cyclooctene oxide was not a suitable substrate under the titanium catalysis, but cyclooctadiene monoepoxide gave product in 54% yield and 91% ee. In this system, the undesired ring opening reaction with isocyanide instead of cyanide was observed as a minor pathway. Mononuclear Ti-salen complexes resulted in much less satisfactory enantioselectivity, suggesting the importance of cooperative functions of the two titanium centers. In a manner similar to that described for other dinuclear catalysts, one titanium center is speculated to act as a Lewis acid to activate the epoxide, while the other delivers cyanide in an intramolecular fashion.

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Scheme 16 Homodinuclear μ-oxo-Ti-L3 catalyst for asymmetric ring opening of meso epoxides with cyanide

Gong and co-workers utilized μ-oxo-bridged bimetallic vanadium–Schiff base complexes for enantioselective oxidative coupling of 2-naphthols. For aerobic oxidation, μ-oxo-bridged dinuclear V-L4 based on an H8-binaphthol scaffold was the best, giving products in 58–99% yield and 60–97% ee (Scheme [17]).[ 38 ] Mechanistic studies suggested that the reaction proceeds via intramolecular radical–radical coupling using two vanadium metals. Sasai and co-workers also reported using the closely related homodinulcar vanadium–Schiff base complexes for oxidative coupling reactions.[ 39 ]

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Scheme 17 μ-Oxo-bridged dinuclear V-L4 catalyst for aerobic enantioselective oxidative coupling of 2-naphthols

# 5

Heterodinuclear Schiff Base Complexes

In sections 2–4, strategies based on linking two privileged 1:1 metal–salen complexes to enhance the cooperative functions between two active sites were discussed. In those studies, the primary focus was on improving the catalyst turnover number and the enantioselectivity achieved with the mononuclear metal–salen catalysts, and studies to use linked metal–salen catalysts to broaden the reaction scope were still limited. In contrast to the above-mentioned strategies, attempts to obtain unique catalytic properties different from mononuclear metal–salen catalysts have led to the design of dinucleating Schiff bases. In sections 5 and 6, heterodinuclear and homodinuclear Schiff base complexes and their application in a variety of asymmetric transformations are described.

In early studies, the addition of a Lewis acidic metal to the mononuclear metal–salen complex was investigated mainly in epoxide-ring-opening reactions,[ 40 ] but the advantages over the simple mononuclear metal–salen complexes were rather limited. An exceptional example is the heterodinuclear Ga-Ti-L1 catalyst (Scheme [18]),[ 41 ] prepared from trimethylgallium and titanium isopropoxide. For the formation of a heterodinuclear complex from L1, the order of metal addition was critical, and trimethylgallium was added first to form an open-form intermediate, followed by the addition of titanium isopropoxide. Attempts to form related heterodinuclear L1 complexes from other group 13 metals were not successful. Zhu and co-workers utilized the heterodinuclear Ga-Ti-L1 catalyst for asymmetric ring opening of meso epoxides with aryl-selenols; 5 mol% of the catalyst gave products in good to high enantioselectivity (Scheme [19]).[ 41 ]

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Scheme 18 Preparation of heterodinuclear Ga-Ti-L1 complex
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Scheme 19 Heterodinuclear Ga-Ti-L1 as catalyst in the desymmetrization of meso epoxides with selenols

To obtain an efficient cooperative bimetallic system, the design of suitable dinucleating ligands is important for placing two metals in appropriate positions. Kozlowski and co-workers designed a dinucleating Schiff base ligand L5 bearing additional 1,1′-bi-2-naphthol units. With the dinucleating ligand L5, the Brønsted basic alkaline metal aryloxide moiety was successfully introduced in addition to the Lewis acidic inner metal center. In the bimetallic system, the selection of two appropriate metals is generally critical for inducing good enantioselectivity. The combination of nickel, cesium, and L5 in a ratio of 1:2:1 was the best for the catalytic asymmetric Michael reaction of dibenzyl malonate to cyclic enones, and products were obtained in up to 90% ee (Scheme [20]).[ 42 ]

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Scheme 20 Catalytic asymmetric Michael reaction promoted by a heterodinuclear Ni-Cs-L5 catalyst

On the basis of precedents in the field of coordination chemistry,[ 43 ] Shibasaki, Matsunaga and co-workers utilized the dinucleating Schiff base L6 bearing additional phenolic hydroxy groups directly attached on the same aromatic ring (Figure [3]).[ 44 ] A combined heterobimetallic transition metal and rare earth metal system was first investigated, because chemoselective complexation of two distinct metals with L6 was possible. The dinucleating Schiff base L6 selectively incorporates a transition metal into the N2O2 inner cavity, and an oxophilic rare earth metal with a large ionic radius into the O2O2 outer cavity.

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Figure 3 Dinucleating Schiff base L6 designed for the construction of a transition metal and rare earth metal bimetallic system.

The selection of a suitable metal combination for each targeted reaction was important for achieving high enantio- and diastereoselectivity. For the syn-selective nitro-­Mannich-type reaction, a heterobimetallic complex prepared from copper(II) acetate, samarium isopropoxide, dinucleating Schiff base L6, and 4-methoxyphenol was the best, giving products in 66–98% ee (Scheme [21]).[ 45 ] The reaction proceeded smoothly even when using readily isomerizable alkyl imines, and the product was applied in the concise catalytic enantioselective synthesis of nemonapride, an anti-psychotic agent. In the nitro-­Mannich-type reaction, other metal combinations resulted in much lower selectivity and/or reactivity. Furthermore, neither the Cu-L6 (1:1) complex nor the Sm-L6 (1:1) complex gave satisfactory reactivity and stereoselectivity, and both copper and samarium metals were important for the unique catalytic properties. The proposed catalytic cycle of the nitro-Mannich-type reaction is shown in Scheme [22]. The samarium–aryloxide unit is likely to act as a Brønsted base to generate samarium nitronate, while the copper(II) would act as a Lewis acid to control the position of the N-Boc imine. Among the possible transition states, the sterically less hindered TS-1 is more favorable. Thus, the stereoselective addition via TS-1 followed by protonation affords syn-product.

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Scheme 21 Postulated structure of the Cu-Sm-L6 catalyst and its application in a nitro-Mannich-type reaction
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Scheme 22 Proposed catalytic cycle for the Cu-Sm-L6 catalyzed ­nitro-Mannich-type reaction

In the bimetallic system, the choice of transition metal and rare earth metal combination drastically affected the chiral environment. The Cu-Sm-L6 catalyst optimized for the nitro-Mannich-type reaction in Scheme [21] was not at all effective when changing electrophiles from imines to aldehydes. Because a variety of chiral environments can be readily constructed using the same chiral ligand L6 just by changing the metal combination, a new optimized metal combination was developed for the reaction with aldehydes. As a result, the combined use of palladium(II) and lanthanum isopropoxide was found to be suitable for the diastereo- and enantioselective Henry reaction. Good to high enantioselectivities and anti-selectivities were achieved as shown in Scheme [23].[ 46 ] The reaction was applied to the concise catalytic asymmetric synthesis of β-adrenoceptor agonists.

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Scheme 23 Heterodinuclear Pd-La-L6 catalyst for the anti-selective Henry reaction and its application to the synthesis of β-adrenoceptor agonists

The dinucleating Schiff base L7, derived from o-vanillin, was used to incorporate a Lewis acidic cationic rare earth metal, RE(OTf)3, into the outer O2O2 cavity instead of a Brønsted basic rare earth metal alkoxide. A heterobimetallic complex prepared from gallium isopropoxide, ytterbium triflate, and L7 was suitable for the α-addition of isocyanide to aldehydes, giving products in 88–98% ee (Scheme [24]).[ 47 ]

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Scheme 24 Heterobimetallic Ga-Yb-L7 catalyst for the asymmetric α-addition of isocyanides to aldehydes

The heterobimetallic Ga-Yb-L7 catalyst gave much better enantioselectivity and reactivity than did the mononuclear metal–salen complexes. The dinucleating ligand L2 was also utilized for combining two distinct rare earth metal sources. The Brønsted basic lanthanum isopropoxide and Lewis acidic ytterbium triflate were successfully placed onto the same dinucleating ligand L2, and the heterobimetallic La-Yb-L2 catalyst was applied to the asymmetric ring-opening reaction of meso aziridines with malonates. The ring-opened adducts were obtained in 63–99% yield and 98–99% ee from cyclic and acyclic meso aziridines (Scheme [25]). The transformation of the ring-opened products into cyclic γ-amino acids, which are useful in foldamer research, was also reported.[ 48 ]

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Scheme 25 Catalytic asymmetric ring opening of meso aziridines promoted by a heterodinuclear rare earth metal and Schiff base catalyst and its application to cyclic γ-amino acid synthesis

Shibasaki and co-workers also expanded the heterobimetallic Schiff base system to include the use of a reduced-type dinucleating amino-phenol ligand L8. A mixture of Ni-La-L8 in a ratio of 1:1:1 was best for the catalytic asymmetric decarboxylative 1,4-addition of a malonic acid half-thioester. The addition of achiral phosphine oxide was effective in improving the reactivity of the catalyst possibly by enhancing the Brønsted basicity of the lanthanum aryloxide moiety, and decarboxylated products were obtained in 40–99% yield and 66–92% ee (Scheme [26]).[ 49 ] The reaction was applied to the catalytic enantioselective synthesis of (S)-rolipram, an anti-­depressant.

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Scheme 26 Catalytic asymmetric decarboxylative 1,4-addition of malonic acid half-thioesters to nitroalkenes and its application to the enantioselective synthesis of (S)-rolipram

# 6

Homodinuclear Schiff Base Complexes

In the heterodinuclear Schiff base catalysts described in section 5, it is important to establish the method of obtaining uniform catalytically active species by selectively placing two different metals into two distinct cavities. If different heterodinuclear complexes exist in equilibrium, that may lead to low enantioselectivity. To simplify the preparation of dinuclear Schiff base complexes, the possible metal combination can be limited to some extent. For example, Shibasaki, Matsunaga and co-workers utilized large and oxophilic rare earth metals as the second metal to be selectively incorporated into the outer cavity (see section 5). Another way to avoid difficulty in the two-­metals-one-ligand complexation process is by using two of the same metal in the design of dinuclear cooperative catalysts. Gao and co-workers utilized dinucleating Schiff base L9, and synthesized a series of bimetallic L9 catalysts, including Co2-L9 and Mn2-L9. The catalytic performance of the bimetallic L9 catalysts was evaluated in an asymmetric cyclopropanation, giving products in up to 94% ee with modest trans/cis selectivity (Scheme [27]).[ 50 ] Several other successful examples, where two of the same metal are placed into two equivalent cavities, have already been discussed in previous sections (see Schemes 7, 16, and 17).[25] [37] [38] [39]

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Scheme 27 Homodinuclear L9 catalyst for asymmetric cyclopropanation

For creating unique catalytic cooperative activity of homodinuclear catalysts different from bimolecular metal-salen (M-L1) cooperative systems, it would be desirable to place the two metals into two distinct cavities because two metals in coordinatively different environments should have different functions. To address this issue, ­Shibasaki, Matsunaga, and co-workers utilized dinucleating Schiff base L10 derived from 1,1′-binaphthyl-2,2′-diamine. Because the size of the O2O2 outer cavity in L10 was smaller than that in related Schiff bases, such as L6, derived from other diamines, various first-row transition metals were successfully incorporated into the O2O2 outer cavity. As shown in Scheme [28], the reaction of the dinucleating Schiff base with two equivalents of Ni(OAc)2·4H2O gave a homodinuclear Ni2-L10 catalyst in 93% yield as a bench-stable solid.[ 51 ] Homodinuclear Co2-L10 and Mn2-L10 catalysts were also synthesized without difficulty.

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Scheme 28 Structure of dinucleating Schiff base L10 derived from 1,1′-binaphthyl-2,2′-diamine, and preparation of homodinuclear catalysts

Homobimetallic L10 complexes were utilized for the asymmetric carbon–carbon bond-forming reactions of pro-nucleophiles bearing a relatively acidic proton. The Ni2-L10 catalyst promoted asymmetric Mannich-type reactions of nitroacetates,[ 51 ] malonates,[ 51 ] β-keto esters,[ 51 ] and β-keto phosphonates[ 52 ] to give products in excellent enantio- and diastereoselectivity (Scheme [29]). As shown in Scheme [30], the mononuclear nickel catalysts resulted in poor reactivity and stereoselectivity. Thus, the use of the homodinuclear Ni2-L10 catalyst was essential for obtaining products in good yield and stereoselectivity. The proposed cooperative mechanism of the reaction with nitroacetate is shown in Scheme [31]. One of the nickel–oxygen bonds in the outer O2O2 cavity works as a Brønsted base to deprotonate the nitroacetate and generate a nickel enolate in situ. The other nickel, in the inner N2O2 cavity, functions as a Lewis acid to control the position of the ­imines. The carbon–carbon bond formation, followed by protonation, affords the Mannich adduct and regenerates the Ni2-L10 catalyst.

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Scheme 29 Ni2-L10 as catalyst in the asymmetric Mannich-type reaction of nitroacetates, malonates, β-keto esters, and β-keto phosphonates
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Scheme 30 Catalytic activity difference between homodinuclear Ni2-L10 catalyst and mononuclear nickel Schiff base catalysts
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Scheme 31 Cooperative Lewis acid and Brønsted base mechanism for homodinuclear Ni2-L10 catalysis

The same Ni2-L10 catalyst was also suitable for the vinylogous Mannich-type reaction of α,β-unsaturated γ-butyrolactams, providing useful building blocks in 99% ee and with syn-selectivities ranging from 5:1 to >30:1 (Scheme [32]).[ 53 ] When 1,2-dicarbonyl compounds were used as the donors, slight modification of the chiral environment – by using the biphenyldiamine framework L11 – was effective, giving products in 91–95% ee and with diastereoselectivities ranging from 10:1 to >50:1.[ 54 ] The Mannich products were utilized for the synthesis of fully substituted azetidine carboxylic acid derivatives as ­unnatural α-amino acids. Stereoselective reduction with K-Selectride, followed by intramolecular Mitsunobu ­cyclization, gave azetidine-2-amides (Scheme [33]).

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Scheme 32 Ni2-L10 as catalyst in the asymmetric vinylogous ­Mannich-type reaction of α,β-unsaturated γ-butyrolactams
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Scheme 33 Biphenyldiamine-based homodinuclear Ni2-L11 catalyst for the asymmetric Mannich-type reaction of 1,2-dicarbonyl compounds, and its application to azetidine-2-amide synthesis

For the catalytic asymmetric Michael reaction to nitroalkenes, the choice of a suitable metal source was important with regard to the structure of the bidentate donors and the position of the reacting carbon (Scheme [34]). (CoIII)2-L10 was the best for asymmetric Michael reaction with β-keto esters,[ 55 ] while (MnIII)2-L10 was utilized in the reaction with N-Boc oxindoles.[ 56 ] On the other hand, Ni2-L10 was the best for asymmetric vinylogous Michael reaction with α,β-unsaturated γ-butyrolactams.[ 57 ] For the reaction with 1,2-dicarbonyl donors, Ni2-L11 gave much better stereoselectivity than Ni2-L10.[ 58 ] The related enantio- and diastereoselective double Michael reaction of N-Boc bisoxindole was applied in the concise catalytic enantioselective total synthesis of hexahydro(pyrrolo)indole alkaloids, such as (+)-chimonanthine (Scheme [35]).[ 59 ] In the double Michael reaction of N-Boc bis-oxindole, manganese(II) 4-fluorobenzoate was utilized instead of manganese(II) acetate in the first Michael reaction. For the second Michael reaction, the chiral Mn-L10 catalyst gave the double Michael product only in moderate yield possibly due to severe steric hindrance toward construction of vicinal quaternary carbon stereocenters; thus, the diastereo­selective reaction with a catalytic amount of manganese(II) acetate was selected as an alternative approach, giving the double Michael adduct in 69% yield, 95% ee, and >20:1 dr. The enantioselective total synthesis of (+)-chimonanthine was achieved in 25% overall yield (5 steps from N-Boc bisoxindole).

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Scheme 34 Catalytic asymmetric Michael reactions of various bidentate donors to nitroalkenes
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Scheme 35 Concise catalytic asymmetric total synthesis of (+)-chimonanthine via double Michael reaction

Other asymmetric carbon–carbon bond-forming reactions, such as the 1,4-addition to alkynones (Scheme [36])[ 60 ] and vinylidenebisphosphonates (Scheme [37]),[ 61 ] and the aldol reaction with formaldehyde,[ 62 ] were also successfully achieved with homodinuclear L10 catalysts. In the catalytic asymmetric 1,4-addition to alkynones, the (CoIII)2-L10 catalyst gave the best results under solvent-free conditions. Because the E/Z ratio was moderate after (CoIII)2-L10 catalyzed addition and protonation process, the crude reaction mixture was directly treated with a catalytic amount of methyldiphenylphosphine to afford predominantly the thermodynamically more favorable E-isomer. In the catalytic asymmetric 1,4-addition of nitroacetates to vinylidenebisphosphonates, the homodinuclear Ni2-L10 catalyst gave the best enantioselectivity. The products in Scheme [37] can be key synthetic intermediates in the preparation of bisphosphonates bearing α-amino acid units, which would be useful for medicinal chemistry.

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Scheme 36 Homodinuclear (CoIII)2-L10 as catalyst in the asymmetric 1,4-addition to alkynones
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Scheme 37 Ni2-L10 as catalyst in the asymmetric 1,4-addition of nitroacetates to vinylidenebisphosphonates

The utility of the homodinuclear Ni2-L10 catalyst was further expanded to reactions other than carbon–carbon bond-forming reactions. Shibasaki, Watanabe, and co-workers achieved the catalytic desymmetrization of 3-methylglutaric anhydride and its derivatives with alcohols, giving hemi-esters in 80–99% yield and 75–92% ee (Scheme [38]).[ 63 ] The reaction was applied in the synthetic studies of caprazamycin B.[ 64 ] Ni2-L10 also promoted the asymmetric amination of N-Boc oxindoles (Scheme [39]),[ 65 ] with catalytic amounts of 1 mol% being sufficient to obtain products in high yield with 87–99% ee. The amination products were readily converted into 3-amino-oxindoles via removal of the Boc group under acidic ­conditions, followed by rhodium-on-carbon catalyzed ­nitrogen–nitrogen bond cleavage.

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Scheme 38 Ni2-L10 as catalyst in the desymmetrization of 3-substituted glutaric anhydrides
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Scheme 39 Ni2-L10 as catalyst in the asymmetric amination of N-Boc oxindoles

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Summary

Multimetallic salen and related Schiff base complexes constitute one of the most powerful classes of emerging cooperative asymmetric catalysts. Drastic improvement in cooperative catalytic activity was observed by linking two mononuclear metal–salen units, leading to higher catalytic activity and/or broader substrate generality under mild reaction conditions. For realizing unique catalytic activities different from those of mononuclear metal–salen complexes, the utility of dinucleating Schiff bases have also attracted much interest recently. The multi­metallic salen and Schiff base cooperative catalysts will likely be involved in various challenging asymmetric transformations, such as the construction of quaternary carbon stereocenters via asymmetric carbon–carbon bond-forming process.


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Acknowledgment

Financial support from the ACT-C program from JST, a Grant-in-Aid for Young Scientist (A) from JSPS, the Naito Foundation, and the Inoue Science Foundation is gratefully acknowledged.



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Figure 1 Dual activation with bimetallic cooperative asymmetric catalysts
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Scheme 1 Postulated bimolecular cooperative mechanism of two Cr-L1 complexes
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Figure 2 Covalently linked dimeric Cr-salen, Al-salen, and Co-salen complexes
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Scheme 2 Catalytic asymmetric 1,4-addition of cyanide to β-alkyl α,β-unsaturated imides with covalently linked dimeric Al-salen complex
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Scheme 3 Catalytic asymmetric intramolecular cyclization of meso epoxy alcohol
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Scheme 4 Oligomeric Co-salen catalyst for hydrolytic desymmetrization of a meso epoxide
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Scheme 5 Chromatography-free synthesis of an oligomeric Co(NBS)-salen catalyst and its application to the kinetic resolution of terminal epoxides
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Scheme 6 Desymmetrization of meso oxetanes using an oligomeric Co-salen catalyst
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Scheme 7 Catalytic, highly isotactic polymerization of terminal epoxides promoted by a bimetallic Co-salen catalyst
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Scheme 8 Supramolecular linkage of two Cr-salen units
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Scheme 9 Catalytic asymmetric Henry reaction with the first-­generation self-assembled dimeric CoII-salen catalyst
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Scheme 10 The second-generation self-assembled dimeric CoIII-salen catalyst, using hydrogen-bonding at the urea moieties, for ­enantio- and diastereoselective Henry reaction
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Scheme 11 Hydrolytic kinetic resolution of racemic terminal epoxides with the self-assembled CoIII(OTs)-salen catalyst
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Scheme 12 Catalytic asymmetric cyanosilylation of aldehydes promoted by μ-oxo-bridged dimeric Ti-L1 complexes
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Scheme 13 Covalently linked μ-oxo Ti-salen dimer for catalytic asymmetric cyanosilylation of aldehydes
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Scheme 14 Dimeric Y-L2 catalyst for asymmetric ring opening of meso aziridines with azide and cyanide
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Scheme 15 Dimeric Y-L2 catalyst for regiodivergent ring opening of racemic terminal aziridines with azide
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Scheme 16 Homodinuclear μ-oxo-Ti-L3 catalyst for asymmetric ring opening of meso epoxides with cyanide
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Scheme 17 μ-Oxo-bridged dinuclear V-L4 catalyst for aerobic enantioselective oxidative coupling of 2-naphthols
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Scheme 18 Preparation of heterodinuclear Ga-Ti-L1 complex
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Scheme 19 Heterodinuclear Ga-Ti-L1 as catalyst in the desymmetrization of meso epoxides with selenols
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Scheme 20 Catalytic asymmetric Michael reaction promoted by a heterodinuclear Ni-Cs-L5 catalyst
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Figure 3 Dinucleating Schiff base L6 designed for the construction of a transition metal and rare earth metal bimetallic system.
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Scheme 21 Postulated structure of the Cu-Sm-L6 catalyst and its application in a nitro-Mannich-type reaction
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Scheme 22 Proposed catalytic cycle for the Cu-Sm-L6 catalyzed ­nitro-Mannich-type reaction
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Scheme 23 Heterodinuclear Pd-La-L6 catalyst for the anti-selective Henry reaction and its application to the synthesis of β-adrenoceptor agonists
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Scheme 24 Heterobimetallic Ga-Yb-L7 catalyst for the asymmetric α-addition of isocyanides to aldehydes
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Scheme 25 Catalytic asymmetric ring opening of meso aziridines promoted by a heterodinuclear rare earth metal and Schiff base catalyst and its application to cyclic γ-amino acid synthesis
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Scheme 26 Catalytic asymmetric decarboxylative 1,4-addition of malonic acid half-thioesters to nitroalkenes and its application to the enantioselective synthesis of (S)-rolipram
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Scheme 27 Homodinuclear L9 catalyst for asymmetric cyclopropanation
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Scheme 28 Structure of dinucleating Schiff base L10 derived from 1,1′-binaphthyl-2,2′-diamine, and preparation of homodinuclear catalysts
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Scheme 29 Ni2-L10 as catalyst in the asymmetric Mannich-type reaction of nitroacetates, malonates, β-keto esters, and β-keto phosphonates
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Scheme 30 Catalytic activity difference between homodinuclear Ni2-L10 catalyst and mononuclear nickel Schiff base catalysts
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Scheme 31 Cooperative Lewis acid and Brønsted base mechanism for homodinuclear Ni2-L10 catalysis
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Scheme 32 Ni2-L10 as catalyst in the asymmetric vinylogous ­Mannich-type reaction of α,β-unsaturated γ-butyrolactams
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Scheme 33 Biphenyldiamine-based homodinuclear Ni2-L11 catalyst for the asymmetric Mannich-type reaction of 1,2-dicarbonyl compounds, and its application to azetidine-2-amide synthesis
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Scheme 34 Catalytic asymmetric Michael reactions of various bidentate donors to nitroalkenes
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Scheme 35 Concise catalytic asymmetric total synthesis of (+)-chimonanthine via double Michael reaction
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Scheme 36 Homodinuclear (CoIII)2-L10 as catalyst in the asymmetric 1,4-addition to alkynones
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Scheme 37 Ni2-L10 as catalyst in the asymmetric 1,4-addition of nitroacetates to vinylidenebisphosphonates
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Scheme 38 Ni2-L10 as catalyst in the desymmetrization of 3-substituted glutaric anhydrides
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Scheme 39 Ni2-L10 as catalyst in the asymmetric amination of N-Boc oxindoles