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Exploring the diversity of dioxyzolines: Why are they the "privileged" ligands of chemistry?
Bis(oxazoline) ligands (BOX ligands for short) are privileged chiral ligands, whose structure contains two oxazoline rings. Such ligands usually have C2 symmetry and exist in a variety of forms, among which CH2 or pyridine chain structures are particularly common. Coordination complexes of dioxazolin ligands are widely used in asymmetric catalysis, and the key to their success lies in their unique structure and synthetic approach.
The chemical reactivity and selectivity of dioxazolin ligands make them indispensable tools in asymmetric catalysis.
Synthesis
The synthesis of oxazolin ring is quite mature, and is usually prepared by cyclization reaction of 2-amino alcohol with a variety of suitable functional groups. In the synthesis of dioxazolin, it is most convenient to use bifunctional starting materials, since this allows the simultaneous generation of two rings. The most commonly used materials are dicarboxylic acids or dicyano compounds. Due to the availability of these materials, most dioxazolin ligands are prepared from these materials. The application of BOX and PyBOX has become more common due to the convenient one-step synthesis using malone nitrile and dipyridinic acid, which are usually inexpensive raw materials in the market.
Catalytic Applications
In general, the stereochemistry of the methyl-bridged BOX ligands is consistent with a distorted planar tetrahedral intermediate based on related crystal structures. The substituent of oxazolidinone at the 4-position blocks one enantiomer of the substrate, leading to asymmetric selectivity. Its application can be seen in many reactions, such as Aldol reaction, Mannich reaction, ene reaction, Michael addition, Nazarov cyclization reaction and isomeric Diels-Alder reaction.
Studies using (benzyloxy)acetaldehyde as the electrophile showed stereochemistry consistent with the carbonyl oxygen being laterally bound and the ether oxygen being axially bound.
Metal complexes containing dioxazolin ligands have shown effectiveness in a variety of asymmetric catalytic transformations and have been the subject of several literature reviews. The neutral nature of dioxazolidinone makes it ideal for use in conjunction with precious metal complexes, with copper complexes being particularly common. Its most important and commonly used application is carbon-carbon bond formation reactions.
Carbon-carbon bond formation reactions
Dioxazolin ligands have demonstrated their effectiveness in a range of asymmetric cycloaddition reactions, starting with the first application of BOX ligands in spinomeric cyclopropanation reactions and extending to 1 ,3-Bipolar cycloaddition and Diels-Alder reaction. Dioxyzoline ligands also perform well in multiple reactions such as Aldol reaction, Michael reaction and ene reaction.
Other Reactions
The success of dioxazolin ligands in spinomeric cyclopropanation reactions has promoted their application in cyclonitrogenation reactions. Another common reaction is hydrosilation, which has seen increasing use since the first use of PyBOX ligands. Beyond this, there are niche applications as fluorination catalysts and Wacker-type cyclizations.
Historical BackgroundOxozoline ligands were first used in asymmetric catalysis as early as 1984, when Brunner et al. demonstrated that they were effective in stereoselective spinosteric cyclopropane reactions in combination with various Schiff groups. At the time, Schiff groups were prominent ligands because they had been used by Noyori in his discovery of asymmetric catalysis in 1968 (for which he and William S. Knowles later won the Nobel Prize in Chemistry). Brunner's research was inspired by Tadatoshi Aratani, who is currently working on selective cyclopropane reactions. Although the performance of the oxazolin ligand was disappointing in the earliest tests, reaching only 4.9% stereoselectivity, Brunner explored the oxazolin ligand again in the course of studying monophenylated diols, leading to The development of chiral pyridyloxyzoline ligands was achieved with an ee of 30.2% (asymmetric enhancement, reaching 45% in 1986 and 1989, respectively).
In the same year, Andreas Pfaltz et al. reported the success of asymmetric spinomeric cyclopropanation using C2-symmetric half-crown ligands with ee as high as 92% to 97%. Although the work of Brunner and Aratani was mentioned, the design of the ligand was also mainly based on his earlier research on various macrocyclic compounds. However, a drawback of these ligands is that they require multi-step syntheses with an overall yield of approximately 30%. Brunner's research led to the development of the first dioxazolins, and Nishiyama synthesized the first PyBox ligand in 1989, which paved the way for achieving results up to 93% ee in bonding reactions. Subsequently, Masamune et al. reported the first BOX ligand in 1990 and obtained a result of up to 99% ee in the copper-catalyzed spinocyclopropane reaction, which was an amazing result at the time and triggered a great interest in BOX ligands. of great interest.
With the in-depth study of the synthesis of 2-oxozoline ring, many related literatures have been published. Today, there exists a considerable number of dioxazolin ligands, most of which are still structurally centered around the classical BOX and PyBOX motifs, but also include some alternative structures, such as axially chiral compounds. The diversity of dioxyzoline ligands makes them play an important role in asymmetric catalysis. Can innovation continue to be challenging in the future?
