A complete overview covering the application of metal-based chiral Lewis acids from all parts of the periodic table, the Author emphasizes the most recent contributions to the field as well as prominent direction of development.
The book discusses the design of chiral complexes as well as a wide spectrum of reactions promoted by various chiral Lewis acids, including water-compatible acids as well as the most important applications in the chemical and pharmaceutical industries.
A must-have for catalytic and organic chemists working in the field, both in academia and industry, as well as pharmaceutical and medicinal chemists.
Jacek Mlynarski is a Professor of Organic Chemistry and Group Leader at the Jagiellonian University of Krakow (Poland). He also studied chemistry at the Jagiellonian University in Krakow and received his Ph.D. (2000) from the Institute of Organic Chemistry of the Polish Academy of Sciences. In 2001 he obtained a research fellowship from the Alexander von Humboldt Foundation and worked with Prof. Alois Fürstner at the Max Planck Institute for Coal Research (Germany). Upon returning to Poland in 2002, he first obtained an academic position at the Institute of Organic Chemistry at the Polish Academy of Sciences, before joining his current department in 2008. His scientific interest includes enantioselective synthetic methodology that relies on metal-based and metal-free chiral catalysts.
Alkaline-Earth Metal-Based Chiral Lewis Acids
Anna Domzalska, Artur Ulikowski and Bartlomiej Furman
Institute of Organic Chemistry, Polish Academy of Sciences, Warsaw, Poland
Catalysis based on transition metal compounds has received considerable attention over the years. In this field, asymmetric catalysis based on chiral Lewis acids is broadly recognized as a significant tool for the preparation of optically active compounds. However, from the perspective of green sustainable chemistry, it is highly preferred to find environmentally friendly processes and catalysts. In contrast to most transition and noble metal complexes, chiral alkaline-earth metal-based catalysts offer high efficiency and stereoselectivity but also less toxicity and less potential for harm. That is why the studies of asymmetric transformations with the use of these novel catalytic systems are attracting ever-growing interest.
1.2 General Properties of Alkaline Earth Metal Compounds
In alkaline-earth metal-catalyzed reactions, the amphoteric acid/base character of the complexes is of extreme importance. The strong Brønsted basicity allows for the abstraction of acidic protons, such as the a-protons of carbonyl compounds. On the other hand, the significant Lewis acidity is used for stereocontrol of the reaction [1-5]. These unique properties of alkaline earth metal complexes are due to the chemical properties of Group II metals. Both the Brønsted basicity and the Lewis acidity are directly connected to the electronegativity of the metals [1, 2, 5]. For this reason, the calcium compounds are weaker Brønsted bases and stronger Lewis acids than barium and strontium complexes when coupled with similar counterions [1, 2, 5]. However, the smaller ionic radius and smaller coordination number of calcium makes it more amenable to chiral modifications than strontium or barium [1, 4, 6]. Moreover, the character of the ligand exerts an influence not only on the asymmetric environment construction but also on the amphoteric acid/base character of the alkaline earth metal compounds. Taking into account the character of ligands and the type of bonds between the metal and the ligand, chiral alkaline earth metal complexes have been classified into three types (Figure 1.1) [1, 2, 5].
Figure 1.1 Types of alkaline earth metal complexes.
In the first type of complexes, the metal is tightly connected to the anionic chiral ligands through covalent bonds. Since these ligands act as Brønsted bases, it is difficult to control the basicity of the catalyst. However, when anionic chiral ligands are bonded to the metal by a combination of one covalent and further coordinative bonds (type II), the Brønsted basicity can be controlled by changing the remaining free counterion [1, 2, 5]. Thanks to the presence of a covalent bond in both type I and type II complexes, there is a possibility for strict control of the asymmetric environment [1, 2, 5].
On the other hand, the construction of chiral alkaline earth metal complexes by attaching a ligand through only coordinative bonds (type III) is also possible [1, 2, 5]. The metal center interacts efficiently with Lewis bases, such as neutral coordinative ligands, owing to its significant Lewis acidity [1, 2, 5]. In such complexes, the two remaining anionic ligands act as effective Brønsted bases. Moreover, the Brønsted basicity of the whole compound should be enhanced by electron donation of the ligands to the metal center [1, 2, 5].
1.3 Applications in Asymmetric Synthesis
Scientists all around the world still carry out research into highly stereoselective reactions including asymmetric transformations which target optically active compounds . One of the most popular approaches in this regard is organocatalysis based on heavy transition metal compounds. However, there is a necessity to find environmentally friendly catalytic systems from the viewpoint of green sustainable chemistry [1, 2, 5, 7]. An alternative path is the use of the chiral alkaline earth metal catalysts [1, 2, 5]. This approach also allows for enantiomeric or diastereomeric enrichment, which is crucial for asymmetric synthesis, but is less environmentally damaging [1-5]. Moreover, the unique chemical properties of Group II metals, such as amphoteric acid/base character, divalent stable oxidation state, and the high coordination numbers to the metal center allow to obtain three types of chiral alkaline earth metal complexes, which collectively find applications in a number of organic reactions [1, 2, 5]. We review many of these applications below.
1.3.1 Cycloaddition Reactions
Some of the fundamental processes in organic chemistry that have been developed over the years are cycloaddition reactions. This type of pericyclic process -->can be used to obtain cyclic adducts and asymmetric versions of such transformations are extremely useful methods to construct highly functionalized derivatives in an optically active form. For instance, asymmetric 1,3-dipolar cycloaddition reactions are some of the most efficient and often used tactics to synthesize five-membered heterocyclic rings, in regio- and stereocontrolled fashion [1, 6, 8, 9]. In particular, [3+2] cycloaddition reactions are a useful method for synthesizing chiral pyrrolidine derivatives, which are important building blocks in the syntheses of many natural products and pharmaceuticals [1, 4, 6]. Several enantioselective metal catalyst systems have been employed to these reactions, but most of these systems require additional bases [1, 10]. This inspired Kobayashi and Yamashita's investigation of asymmetric [3+2] cycloaddition reactions using chiral calcium catalysts [4, 10-13]. They successfully applied chiral Box-calcium complexes to reactions of glycine Schiff bases with ß-substituted a,ß-unsaturated esters, such as methyl crotonate (Scheme 1.1), and obtained the desired chiral pyrrolidine derivatives with high yields, complete diastereoselectivities, and excellent enantioselectivities (Table 1.1) [10-12].
Scheme 1.1 A Box-calcium complex-catalyzed [3+2] cycloaddition reaction of amino acid Schiff bases with a,ß-unsaturated carbonyl compounds [1, 4].
Table 1.1 Asymmetric [3+2] cycloaddition of a glycine ester Schiff base with a,ß-unsaturated carbonyl compounds . Entry R
2 Ligand Time (h) Yield (%) ee (%)
1 MeO Me 1
3 Quant. >99 2 EtO Me 1
3 98 98 3 t
BuO Me 1
3 77 87 4 MeO Et 2
24 Quant. 95 5 MeO i
24 Quant. 99 6 MeO n
48 97 >99 7 NMe2 H 1
12 83 95 8 H 1
24 76 98 9 H 1
24 84 97 10 c
Hex H 1
24 93 91
However, the results of their research indicate that the size and character of the substituent in the aldehyde part of the imine could play an important role in the enantioselectivity of the Box-calcium complex-catalyzed [3+2] cycloaddition reactions [1, 3, 5]. In comparison with glycine Schiff bases that are prepared from aromatic aldehydes (Table 1.1, entries 1-10; Table 1.2, entries 1-10), aliphatic aldehyde derivatives (Table 1.2, entries 11-12) are less stable. This stems from possible tautomerization processes which lead to the formation of enamines. These competitive processes could be crucial in Kobayashi's group research. Moreover, aromatic substituents form better stabilized carbocations, which shifts the equilibrium of the reaction toward the formation of the cyclic adducts and induces higher enantioselectivity.
Table 1.2 Asymmetric [3+2] cycloaddition of a Schiff base of a glycine ester with t-butyl crotonate . Entry R Ligand Time (h) Temperature (°C) Yield (%) ee...