A New Heterocyclic Chiral Ligand, 4,6-Dibenzofurandiyl-2,2'-bis(4-phenyloxazoline). Effective Catalysis in Diels-Alder Reactions and Some 1,3-Dipolar Cycloadditions

A New Heterocyclic Chiral Ligand, 4,6-Dibenzofurandiyl-2,2'-bis(4-phenyloxazoline). Effective Catalysis in Diels-Alder Reactions and Some 1,3-Dipolar Cycloadditions

Shuji KANEMASA

Institute of Advanced Material Study, Kyushu University , 6-1 Kasugakoen, Kasuga 816, Japan
Phone/Fax: +81-92-583-7802, E-Mail: kanemasa@cm.kyushu-u.ac.jp
URL: http://www.cm.kyushu-u.ac.jp/dv01/dv01e.html

Content

===== 1. Expectation III 2. Background III 3. Abstract of Results III 4. Conclusion III 5. Aspect in Future =====

1. Expectation
Although many examples have been reported for the chiral Lewis acid catalysts that show effective catalytic activity resulting in high enantioselectivities, there are some other features of catalytic process that remain to be improved. One undesirable but inevitable nature of catalyst complexes is the formation of oligomeric aggregation which often affects the catalytic activity. Accordingly, appropriate structural design to avoid such aggregation is a worthwhile goal; monomeric structures of catalysts would lead to an enhanced catalytic activity. The second desirable characteristic is the stability of catalyst complexes; assistance to protic media such as water, alcohols, acids and amines is highly beneficial. Liability in protic media is usually observed for traditional Lewis acid catalysts, restricting their use in catalyzed asymmetric reactions under protic conditions.

cis-Chelating ligands have been frequently used for the chiral modification of Lewis acid catalysts. In cis-complexes, the metallic center tends to be exposed to the undesired access of other molecules of ligand and complex itself. Oligomer formation becomes easy and this usually occurs. Our idea to avoid this aggregate formation involves the employment of a tridentate trans-chelating ligand. Use of neutral ligands such as bisoxazoline types seems to be favorable because of the following reasons:
(1) Coordination of three anionic ligands to a metallic center will reduce the Lewis acidity of the metallic center. The combination of neutral tridentate ligands with noncoordinating anionic ligands produces cationic complexes which may maintain a high catalytic activity.
(2) Competitive coordination between a chiral ligand and a substrate is generally a challenging problem; if the substrate completely displaces the chiral ligand, an achiral catalyst can result. Tridentate ligands are expected to increase the stability of complex structure with respect to ordinary bidentate ligands.
(3) We have learned from the molecular modeling inspection that the trans-chelating structure by two oxazoline moieties, especially when these two heterocyclic rings are coplanar, provides an attractive chiral space around the metallic center. Some effective enantioselectivity is anticipated in the catalyzed reactions.
(4) The metal included in the above model complex is located in the middle of the chiral structure surrounded by the chiral ligands, so that aggregation is disfavored.

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2. Background
Despite these attractive features, there are only a few examples of effective catalysts that bear trans-chelating tridentate ligands. Homogeneous catalysts including transition metals of low oxidation levels have been used as Lewis acid catalysts. Pioneering work by Bosnich and coworkers has recently unveiled a new category of transition metal Lewis acid catalysts. Some aqua complexes of titanium and ruthenium salts are highly air-stable and water-tolerant. These show high catalytic activity and effective turnover numbers of catalytic cycle in Diels-Alder reactions of alpha,beta-unsaturated carbonyl dienophiles. This suggests that the aqua ligands can be very rapidly replaced with dienophiles even in the presence of additional water. An enantiopure titanium catalyst with aqua ligands, as well as some anhydrous titanium and zirconium complexes, has achieved reasonable enantioselectivities.

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3. Abstract of Results
A Diels-Alder Reaction
A01 Diels-Alder reactions
B Structure and Stability of Complex Catalyst
B01. Ligand synthesis III B02 Preparation of DBFOX/Ph complexes III B03 Water tolerance III B04 Competitive coordination III B05 Transition structure
C Chiral Amplification
C01 Chiral amplification III C02 Mechanism 01 III C03 Mechanism 02 III C04 Effect of coordinating additives
D 1,3-Dipolar Cycloaddition
D01 Nitrone cycloadditions III D02 Role of MS 4A and transition structure) III D03 Diazo cycloadditions III D04 Chelate auxiliary

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4. Conclusion
Cationic aqua complexes prepared from (R,R)-4,6-dibenzofurandiyl-2,2'-bis(4-phenyloxazoline) (called DBFOX/Ph) and metal(II) perchlorates such as magnesium, nickel, iron, cobalt, copper, and zinc ions, show a high catalytic activity. They induce absolute enantioselectivity in the Diels-Alder reactions of cyclopentadiene with 3-alkenoyl-2-oxazolidinones. The DBFOX/Ph complex of Ni(ClO4)´6H2O is isolated as a formula of DBFOX/Ph´Ni(ClO4)2´3H2O which can be stored in air for months without loss of catalytic activity. In some cases the aqua complexes are even more active than the anhydrous complexes. Alcohols, acids, and amines do not affect seriously the catalytic activity as well as the enantioselectivity. A remarkable chiral amplification is attained through two mechanisms: the irreversible formation of insoluble meso-2:1 complex and the hydrogen bond mediated oligomer formation among heterochiral enantiomers of 1:1 complexes. Such exceptionally high stability, effective chiral control, and remarkable chiral amplification apparently depend upon the following new features: (1) the size-fitted tridentate cavity of the DBFOX ligand, (2) the trans-chelating structure bearing the metal ion deeply incorporated in its chiral cleft, (3) the exsistence of aqua ligands, (4) the irreversible formation of meso-2:1 complexes, (5) the water-bridged heterochiral oligomerization of 1:1 complexes.

The DBFOX/Ph ligand and its complexes of transition metal perchlorates must be promising from the following points of view:
(1) Easy and inexpensive availability of the ligand
(2) Absolute chiral induction in a Diels Alder reaction and 1,3-dipolar cycloadditions
(3) Rare aqua complex catalysts
(4) High catalytic activity
(5) Generality for metal ions (Ni, Co, Fe, Cu, Zn, Mn, Mg)
(6) Isolation and long term storage in open air
(7) High tolerance to water, alcohols, acids, and amines
(8) Easy estimation of the transition state structure
(9) Remarkable chiral amplification
(10) Irreversible formation of heterochiral 2:1 complexes
(11) Water-bridged oligomerization of heterochiral 1:1 complexes

We believe the present work has shown a new guiding principle for the structural design of chiral ligands and catalysts. Especially the importance of tridentate ligands, trans-chelating structure, aqua complex of transition metals shoud be emphasized. These new complexes may open a new entry to chiral protonic acid catalysts as well as base catalysts. Works along this line are now ongoing in our laboratory.

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5. Aspect in Future
DBFOX/Ph Complexes of transition metal perchlorates are found to be useful for catalyzed enantioselective reactions using 3-(2-alkenyl)-2-oxazolidinones and 1-(2-alkenyl)pyrazoles. Three types of enantioselective ring-forming reactions (Diels-Alder reactions, nitrone cycloadditions, and diazo cycloadditions) have been successfully investigated. In these reactions, two bonds are formed concertedly both at the alpha- and beta-carbons of alkene dienophiles (or dipolarophiles). The trans-chelating DBFOX/Ph ligand is powerful in such types of enantioselective reactions, and hence we plan to extend to some more 1,3-dipolar cycloadditions.

The DBFOX/Ph complexes are highly tolerant against protic nucleophiles such as water, acids, and bases. This feature should be applied to open new catalyzed asymmetric reactions in which both nucleophiles and electrophiles are separatedly activated by a base and the Lewis acid catalyst, respectively. The candidate reaction is the DBFOX/Ph complex catalyzed conjugate additions. Therein 3-(2-alkenyl)-2-oxazolidinones are activated by coordination to the DBFOX/Ph complexes and the nucleophiles are activated by deprotonation by a base. From our preliminary results, conjugate additions of amine and thiol nucleophiles look like promising.

The metal center of DBFOX/Ph - metal complexes have meridional three vacant positions so that the coordination patterns of substrates become very simple. In other words, the number of isomers possible for substrate complexes is limited, which is convenient as asymmetric catalyst. For example, two stereoisomers are possible for the substrate complex of 3-crotonoyl-2-oxazolidinone when the complex has square bipyramid structure, and only one when the complex has trigonal bipyramid structure. This simple structure may be utilized in the fine tuning of enantioselectivity of the DBFOX/Ph complex catalyzed reactions. If one wants to have an open space around the reaction site, like in the concerted ring forming reactions, the square bipyramid structure is more favored. On the other hand, trigonal bipyramid structure is more favored if one wants to have a rather restricted asymmetric space. The conjugate additions proceeding through nonchelation transition strucutr are the cases. But how can we achieve it? The chelate auxiliary such as 2-oxazolidinone is the position of attension. By an appropriate structural design of chelate aukiliaries, we should be able to (1) modify the structure of substrate complexes, and (2) this structural modification shoul be related with the catalytic activity of the catalyst.

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