Ligands for Asymmetric Catalysis

Enantioselective catalysis exemplifies how a complex synthetic route to a chiral molecule can be simplified by catalytic methods, reducing the overall amount of waste and increasing yields. Only a few of the metal-catalyzed reactions have yet been applied industrially, mostly for the synthesis of pharmaceuticals, vitamins, agrochemicals, flavours and fragrances. They include, asymmetric oxidation, hydrogenation, isomerization, hydroformylation, and cyclopropanation (Chapters 2, 3, 4 and 5 Sections 2.7, 3.5, 3.6, 3.7, 4.6.7, 5.6). 

On this basis the choice of a specific catalytic step is usually determined by an economic analysis of the catalytic route vi. alternative routes (such as the separation of enantiomers by resolution, organic synthesis starting from chiral natural products used as building blocks (the chiral pool concept), or the use of enzymatic and microbial transformations) and time to market considerations (see also Chapter 1). 

The following critical factors determine the viability of an enantioselective process  

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Borane complexes of P-heterocycles as versatile precursors for the synthesis of chiral phosphine ligands for asymmetric catalysis 98S1391. 

Kagan HB (1985) Chiral ligands for asymmetric catalysis. In Morrison JD (ed) Asymmetric synthesis, vol 5. Academic Press, New York, chap 1... 

Chiral amines and diamines are readily available substrates for the synthesis of ligands for transition metal-catalysed reactions since they can easily be transformed into chiral ureas and thioureas. Therefore, several groups have prepared chiral symmetrical ureas and thioureas, dissymmetrical ureas and thioureas, amino-urea and thiourea derivatives. Finally polyureas and non-soluble polythioureas were also prepared and tested as ligands for asymmetric catalysis. 

Chuzel O, Riant O (2005) Sparteine as a Chiral Ligand for Asymmetric Catalysis. 15 59-92 Clayden J (2003) Enantioselective Synthesis by Lithiation to Generate Planar or Axial Chirality. 5 251-286... 

The same group of workers has prepared ferrocene derivatives 39 as chiral ligands for asymmetric catalysis. Again, cyclic sulfates of optically pure 1,3-diols were used as reagents in the preparation <99SL1975>. 

For general application of these chiral ligands, see (a) Kagan, H. B. Chiral Ligands for Asymmetric Catalysis in Morrison, J. D. ed. Asymmetric Synthesis, vol. 5, Chap. 1, Academic Press, New York, 1985. (b) Kagan, H. B., Sasaki, M. Optically Active Phosphines Preparation, Uses and Chiroptical Properties in Hartley, F. R. ed. The Chemistry of Organo Phosphorous Compounds, John Wiley Sons, New York, 1990, vol. 1, Chap. 3. 

H. B. Kagan, Chiral Ligands for Asymmetric Catalysis, in Asymmetric Synthesis, Vol. 5 (Ed. J. D. Morrison), Academic Press, London, 1985, pp. 1-40. 

G. Helmchen, A. Pfaltz, Phosphinooxazolines - A New Class of Versatile, Modular RN-Ligands for Asymmetric Catalysis, Acc Chem. Res. 2000, 33, 336-345. 

Scheme 2.55 The combinatorial preparation of schiff bases as ligands for asymmetric catalysis.

Carbohydrates remain an attractive source of chirality in preparation of ligands for asymmetric catalysis. Functionalized phospholanes, 192 [167], and chiral bisphosphinites 193 [168] with an attached crown ether unit were obtained recently from D-mannitol and from phenyl 2,3-di-0-allyl-4,6-0-benzylidene-p-D-glucopyranoside, respectively (Figure 18). Compounds 194 and 195 were obtained in the photochemical addition of H2P(CH2)3PPH2 onto the crresponding alkenes - Pd-complexes of these new bisphosphines were successfully applied as catalysts in the copolymerization of CO and... 

Another significant development in oxazoline chemistry is the application of oxazoline-containing ligands for asymmetric catalysis, such as palladium-catalyzed allylic substimtions, Heck reactions, hydrogenations, dialkylzinc additions to aldehydes, and Michael reactions. The discovery of diastereoselective metalation of chiral ferrocenyloxazolines has further expanded the availability of chiral ligands for metal-catalytic reactions. 

Chuzel O, Riant O (2005) Sparteine as a Chiral Ligand for Asymmetric Catalysis. 25 ... 

Quinazolines take part in the same types of reactions as pyrimidines, but because of their additional benzene ring, the products of these reactions may have the added feature of hindered rotation. An example of this is the synthesis of 2-phenyl-Quinazolinap by Guiry and co-workers <99TA2797>. Suzuki coupling of 4-chloro-2-phenylquinazoline (115) with boronic acids 116 led to 117 (R = OMe). These intermediates were parlayed into phosphinamines 117 (R = PPh2) and then subjected to chiral resolution to produce new chiral phosphinamine ligands for asymmetric catalysis. 

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