Single-enantiomer drugs represent an increasingly large share of new chemical entities, leading to approaches in asymmetric synthesis. Asymmetric hydrogenation is an atom economical and scaleable method for the manufacture of commercial chiral compounds. Developing efficient methods to produce the chiral ligands and catalysts on a large scale is essential to effectively commercialize this technology. The authors examine methods to manufacture select catalyst systems and their application in commercial-scale asymmetric hydrogenation.
Evolution of the technology
During the 1970s, there were no more than a handful of chiral ligands reported, and none of these were commercially available on large scale. The ligand system and synthesis for any given application had to be developed de novo, thereby creating significant barriers in using asymmetric hydrogenation. Most systems also were neither modular nor widely applicable over a broad range of substrates, making systematic selection of a suitable catalytic system difficult to predict. Noyori introduced the BINAP catalysts in the 1980s, and these catalysts led to Takasago developing many commercial processes for manufacturing β-hydroxy esters [used in the Lipitor (atorvastatin) side chain], alcohols, and carbapenem intermediates using ruthenium-BINAP systems (2).
During this period, a greater range of catalytic systems and substrates was established, so systematic employment of chiral catalytic technology was possible to a significantly greater extent. The largest-scale rhodium-BINAP process is the allylic isomerization of diethylgeranylamine to provide (R)-citronellal, an intermediate used to manufacture (–)-menthol, which is produced on a scale exceeding 1000 metric tons per year (2).
The commercial success of the BINAP technology encouraged many companies and research institutes to search for novel ligands outside the scope of the BINAP patents. Hoffmann-La Roche, for example, developed the MeO-BIPHEP ligands and catalysts and applied these ligands in the manufacture of vitamins and pharmaceutical intermediates. The side chain of tetrahydrolipstatin (orlistat) (see Figure 1) is manufactured using an asymmetric hydrogenation process, with a ruthenium MeO-BIPHEP catalyst (3).