Enantioselective synthesis asymmetric hydroformylation

Since the discovery and development of highly efficient Rh catalysts with chiral diphosphites and phosphine-phosphites in the 1990s, the enantioselectivity of asymmetric hydroformylation has reached the equivalent level to that of asymmetric hydrogenation for several substrates. Nevertheless, there still exist substrates that require even further development of more efficient chiral ligands, catalyst systems, and reaction conditions. Diastereoselective hydroformylation is expected to find many applications in the total synthesis of complex natural products as well as the syntheses of biologically active compounds of medicinal and agrochemical interests in the near future. Advances in asymmetric hydrocarboxylation has been much slower than that of asymmetric hydroformylation in spite of its high potential in the syntheses of fine chemicals. 

Claver C, Dieguez M, Pamies O, Castillon S (2006) Asymmetric Hydroformylation. 18 35-64 Clayden J (2003) Enantioselective Synthesis by Lithiation to Generate Planar or Axial Chirality. 5 251-286... 

In spite of extensive studies on the asymmetric hydroformylation of olefins using chiral rhodium and platinum complexes as catalysts in early days, enantioselectivity had not exceeded 60% ee until the reaction of styrene catalyzed by PtCl2[DBP-DIOP (l)]/SnCl-> was reported to attain 95% ee in 1982 [8]. Although the value was corrected to 73% ee in 1983 [9], this result spurred further studies of the reaction in connection to possible commercial synthesis of antiinflammatory drugs such as (S)-ibuprofen and (S)-naproxen. The catalyst PtCl2[BPPM... 

Bisphosphite ligands were originally discovered at Union Carbide and have been extensively studied for olefin hydroformylation. Structural modification of bisphosphite ligands allows their use in asymmetric catalysis. These chiral bisphosphites lead to the highest combination of branched regioselectivity (b/1) and enantioselectivity (%ee) of any asymmetric hydroformylation catalyst reported to date. These catalysts have been applied to a highly efficient synthesis of... 

We describe the extension of this class of bisphosphite catalysts to asymmetric hydroformylation and hydrocyanation of vinylarenes.(3) These enantiose-lective catalytic transformations are employed for the asymmetric synthesis of S-Naproxen, a widely used non-steroidal anti-inflammatory drug (NSAID). Factors which influence regioselectivity and enantioselectivity, as well as characterization of the catalyst resting states, are discussed. 

Continuous, selective hydroformylation in supercritical CO2 using (acac)Rh(CO)2 immobilized on silica as catalyst shows certain advantages. A version of asymmetric hydroformylation in this medium has also been reported,. (Subcritical CO2 gas accelerates solventless synthesis involving solid reactants, including hydrogenation and hydroformylation.) The regioselective and enantioselective nickel-catalyzed hydrovinylation of styrenes in supercritical CO2 make 3-arylpropenes available in an optically active form. " Improvement in the performance of the Pauson-Khand reaction in supercritical media... 

Such imines can be used as ligands for catalytic enantioselective hydrosilylation of ketones (Section D.2.3.1.4) or asymmetric hydroformylation [Section D.l.5.8. which uses (.S)-/V-(2-hy-droxybenzylidene)-l-phenylethylamine (2) " ] or reduced further to chiral amines, e.g.. by sodium borohvdridc4. A convenient one-pot synthesis of such secondary amines uses sodium cyanoborohydride as the reducing agent6. 

The following discussion is to some extent ordered in increasing complexity of alkene substrate and is focused on enantioselective hydroformylations that are known to deliver biologically active compounds, pharmaceutical intermediates, and natural products. All of these examples stem from research laboratories because it is only very recently that asymmetric hydroformylation has been offered as a viable tool for manufacturing-scale asymmetric synthesis, and such applications are eagerly awaited. 

Asymmetric hydroformylation allows the conversion of olefins into optically active aldehydes in a single step. From the point of view of synthesis of optically active pharmaceutical intermediates and fine chemicals, this reaction is of considerable interest. As shown by reactions 5.4.1 and 5.4.2, hydroformylations of 1,2- and 1,1-disubsti-tuted alkenes can lead to the formation of four possible stereoisomers. To be useful, asymmetric hydroformylation must therefore be both regio- and enantioselective. 

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). 

---