Enantioselective Synthesis - Enantioselective Catalysis

Enantioselective Catalysis

The oldest enantioselective synthesis is the enantioselective decarboxylation of the malonic acid 2-ethyl-2-methylmalonic acid mediated by brucine (forming the salt) as reported by Willy Marckwald in 1904:

Small amounts of chiral, enantiomerically pure (or enriched) catalysts promote reactions and lead to the formation of large amounts of enantiomerically pure or enriched products. Mostly, Several different kinds of chiral catalysts are employed:

1. metal ligand complexes derived from chiral ligands
2. chiral organocatalysts
3. biocatalysts.
4. chiral Lewis acids

The first methods were pioneered by William S. Knowles and Ryōji Noyori (Nobel Prize in Chemistry 2001). Knowles in 1968 replaced the achiral triphenylphosphine ligands in Wilkinson's catalyst by the chiral phosphine ligands P(Ph)(Me)(Propyl), thus creating the first asymmetric catalyst. This experimental catalyst was employed in an asymmetric hydrogenation with a modest 15% enantiomeric excess result. The methodology was ultimately used by him (while working for the Monsanto Company company) in an enantioselective hydrogenation step in the industrial production of L-DOPA:

In the same year and independently, Noyori published his chiral ligand for a cyclopropanation reaction of styrene. In common with Knowles' findings, Noyori's results for the enantiomeric excess for this first-generation ligand was disappointingly low: 6%.

Examples of enantioselective catalysis include:

• BINAP, a chiral phosphine, used in combination with compounds of ruthenium or rhodium. These complexes catalyse the hydrogenation of functionalised alkenes well on only one face of the molecule. This process also developed by Ryōji Noyori is commercialized as the industrial synthesis of menthol using a chiral BINAP-rhodium complex.
• The other part of that Nobel prize concerned the Sharpless bishydroxylation
• Naproxen is synthesized with a chiral phosphine ligand in a hydrocyanation reaction
• asymmetric catalytic reduction and oxidation