Asymmetric hydrogenation diphosphines

Monsanto s commercial route to the Parkinson s drug, L-DOPA (3,4-dihydroxyphenylalanine), utilizes an Erlenmeyer azlactone prepared from vanillin. The pioneering research in catalytic asymmetric hydrogenation by William Knowles as exemplified by his reduction of 24 to 25 in 95% ee with the DiPAMP diphosphine ligand was recognized with a Nobel Prize in Chemistry in 2001. ... 

In 2000, these authors also developed a very efficient diphosphine-bithiophene ligand, tetraMe-BITIOP, which is depicted in Scheme 8.29. The ruthenium complex of this electron-rich diphosphine was used as the catalyst in asymmetric hydrogenation reactions of prostereogenic carbonyl functions of a-... 

Manufacture of rhodium precatalysts for asymmetric hydrogenation. Established literature methods used to make the Rh-DuPhos complexes consisted of converting (1,5-cyclooctadiene) acetylacetonato Rh(l) into the sparingly soluble bis(l,5-cyclooctadiene) Rh(l) tetrafluoroborate complex which then reacts with the diphosphine ligand to provide the precatalyst complex in solution. Addition of an anti-solvent results in precipitation of the desired product. Although this method worked well with a variety of diphosphines, yields were modest and more importantly the product form was variable. The different physical forms performed equally as well in hydrogenation reactions but had different shelf-life and air stability. 

Manufacture of ruthenium precatalysts for asymmetric hydrogenation. The technology in-licensed from the JST for the asymmetric reduction of ketones originally employed BINAP as the diphosphine and an expensive diamine, DAIPEN." Owing to the presence of several patents surrounding ruthenium complexes of BINAP and Xylyl-BINAP, [HexaPHEMP-RuCl2-diamine] and [PhanePHOS-RuCl2-diamine] were introduced as alternative catalyst systems in which a cheaper diamine is used. Compared to the BINAP-based systems both of these can offer superior performance in terms of activity and selectivity and have been used in commercial manufacture of chiral alcohols on multi-100 Kg scales. 

In contrast, synthesis of 3,4-diphosphorylthiophenes requires more elaboration because of low reactivity of 3,4-positions of thiophene and unavailability of 3,4-dihalo or dimetallated thiophenes. Minami et al. synthesized 3,4-diphosphoryl thiophenes 16 as shown in Scheme 24 [46], Bis(phosphoryl)butadiene 17 was synthesized from 2-butyne-l,4-diol. Double addition of sodium sulfide to 17 gave tetrahydrothiophene 18. Oxidation of 18 to the corresponding sulfoxide 19 followed by dehydration gave dihydrothiophene 20. Final oxidation of 20 afforded 3,4-diphosphorylthiophene 16. 3,4-Diphosphorylthiophene derivative 21 was also synthesized by Pd catalyzed phosphorylation of 2,5-disubstituted-3,4-dihalothiophene and converted to diphosphine ligand for Rh catalysts for asymmetric hydrogenation (Scheme 25) [47],... 

In summary, the asymmetric hydrogenation of olefins or functionalized ketones catalysed by chiral transition metal complexes is one of the most practical methods for preparing optically active organic compounds. Ruthenium and rhodium-diphosphine complexes, using molecular hydrogen or hydrogen transfer, are the most common catalysts in this area. The hydrogenation of simple ketones has proved to be difficult with metallic catalysts. However,... 

Synthesis of a cylindrically chiral diphosphine and asymmetric hydrogenation of dehydroamino acids... 

SYNTHESIS OF A CYLINDRICALLY CHIRAL DIPHOSPHINE AND ASYMMETRIC HYDROGENATION OF DEHYDRO AMINO ACIDS... 

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