By the 1990s, there were many more catalyst systems established for asymmetric hydrogenation, applying a diverse range of
ligands, using rhodium, ruthenium, and iridium metals, and finding applications in pharmaceutical, agrochemicals, nutraceuticals
and the flavor and fragrance industries. The two ligand systems with the greatest impact developed in the 1990s were DuPhos
(1,2-bis(2,5-dialkylphospholano)benzene) by Burk (4) and Josiphos by Togni and Spindler (5). The JosiPhos ligand system is
used in the largest-scale asymmetric hydrogenation process known to date: for the manufacture of the herbicide Dual Magnum[(S)-metolachlor] (see Figure 1), which is produced on a 20,000-metric-ton scale per year (6). The actual iridium Josiphos catalyst
required was not known at the start of the research project, but was discovered as the development of (S)-metolachlor proceeded. Chirotech, now part of Dowpharma, obtained the exclusive license to the DuPhos, BPE (1,2-bis(2,5-diphenylphospholano)ethane)
and 5-Fc (1,1'-bis (2,5-diphenyl-phospholano) ferrocene) technology for commercial pharmaceutical applications from DuPont.
Chirotech subsequently developed numerous asymmetric hydrogenation processes, and the DuPhos ligands and catalysts were also
offered for sale on commercially relevant scales (>100 g–multi-kilograms) (7).
There are in excess of 3000 ligands known for asymmetric hydrogenation processes, though only a handful of these are truly
available on a kilogram scale within a reasonable lead time (8). Four drugs, recently approved by FDA are reported to use
asymmetric hydrogenation in their manufacture (see Figure 2). Rozerem (ramelteon) (9) and Aptivus (tipranavir) (7) were approved
in 2005, Januvia (sitagliptin) (10) in 2006, and Tekturna (aliskiren) (11) in 2007. These approvals confirm that asymmetric
hydrogenation has matured and become an accepted addition to commercially relevant technologies for pharmaceutical manufacture.
Rhodium DuPhos applications and ligand synthesis
The DuPhos technology has a broad substrate scope, and Chirotech has reported asymmetric hydrogenation processes for tipranavir
(7), candoxatril (7), pregabalin (7), unnatural α-amino acids (12), and succinates (13) (see Figure 3). To further develop
and potentially commercialize such processes, however, require the Me-or Et-DuPhos rhodium precatalysts to be produced on
Prior to the commercialization of the DuPhos technology, Chirotech developed methods to produce the ligands and catalysts
on a multigram scale, with practical but moderate yields. These methods satisfied the laboratory scale and early development
needs for the compounds shown in Figure 3. As demand for these catalyst systems increased toward multi-100s grams and then
to kilograms, it was clear that the initial synthetic methods were not practical in terms of yield, purity, and economics.
In the first instance, Chirotech addressed the ligand synthesis and made improvements over the original routes. Hexane-2,5-diol
was originally obtained using an electrochemical Kolbe coupling of single enantiomer 3-hydroxybutyric acid, but this method
did not scale up well with severe fouling of the electrodes being observed (14).
Chirotech then developed an in-house method constituting a bioresolution approach starting with the 1:1 racemic/meso diol
(15). Using inversion techniques on a monobutyrate derived from the meso diol, a good yield of the (R, R) enantiomer was obtained, but the yield of the (S, S) entantiomer was lower. With the introduction of highly efficient alcohol dehydrogenase enzymes and ready availability of
hexane-2,5-dione, both enantiomers of hexane-2,5-diol are commercially available on the requisite scales. For security of
supply reasons, Dowpharma still operates its own protected bioresolution route.