S-Metolachlor

An even more impressive example of catalytic efficiency has recently been disclosed by Novartis (Bader and Bla.ser, 1997). The key step in a proce.ss for the synthesis of the optically active herbicide, (S)-metolachlor involves asymmetric hydrogenation of a prochiral imine catalysed by an iridium-ferrocenyldipho-sphine complex (see Fig. 2.36). 

The substrate/catalyst ratio is 75,000, and one million turnovers are achieved in six hours, giving a product with an ee of 80%. A higher ee can be obtained, at lower substrate/catalyst ratios, but are not actually necessary for this product. This process will be used to produce several thousands tons per annum of (S)-metolachlor, to replace the previously marketed racemic metolaclor. 

Optically active drugs now occupy centre stage status and some agrochemicals like (S)-metolachlor, have also been introduced as optically pure isomers, so that the ballast of the unwanted isomer is avoided. Asymmetric synthesis is a topic of great interest in current research, and there is a steady flow of articles, reviews and books on almost every aspect of this subject. Table 4.8 lists examples of industrially important asymmetric synthesis. 

Dupont s DuPhOS catalyst A.symmetric hydrogenation for making S-metolachlor Blaser and Spindler... 

Enantiomerically pure amines are extremely important building blocks for biologically active molecules, and whilst numerous methods are available for their preparation, the catalytic enantioselective hydrogenation of a C=N bond potentially offers a cheap and industrially viable process. The multi-ton synthesis of (S)-metolachlor fully demonstrates this [108]. Although phospholane-based ligands have not proven to be the ligands of choice for this substrate class, several examples of their effective use have been reported. 

The formation of dimers and trimers is a major issue in hydrogenations with iridium catalysts. In the context of developing an industrial process to produce (S)-metolachlor via an enantioselective imine hydrogenation (see Chapters 34 and 37), Blaser et al. investigated the causes of catalyst deactivation in the iri-dium/bisphosphine-catalyzed hydrogenation of DMA imine (Scheme 44.11) [84]. 

Togni and Spindler introduced non-C2-symmetric ferrocene-based Josiphos-type ligands [47], which are effective for rhodium-catalyzed hydrogenation of a-(acetami-do)cinnamate, dimethyl itaconate, and / -keto esters. The Josiphos-type hgands have been applied as the stereodefming step in a number of industrial processes, as exemplified the use of PPF- Bu2 for the commercial synthesis of (-i-)-biotin [48], and Xyli-Phos for the preparation of the herbicide (S)-metolachlor [49]. 

Quite a wide range of substrates 100 could be converted into products 101 with high ee values since it is known that the N-protecting group of 101 can easily be cleaved, the approach represents a formal synthesis of optically active amines. It remains to be seen if this iridium/sulfoximine combination also opens up an alternative access to industrially relevant products such as the herbicide (S)-metolachlor produced by Syngenta [80]. 

Blaser, H.-U. The Chiral Switch of (S)-Metolachlor A Personal Account of an Industrial Odyssey in Asymmetric Catalysis. Adv. Synth. Catal. 2002, 344, 17-31. 

Figure 7.32 Chiral reduction to (S)-metolachlor with organometallic catalyst.

A combination of metolachlor (Dual ) and atrazine in a liquid prepack called Bicep facilitated the growing practice of mixing atrazine with grass herbicides. Test marketed in 1978 and 1979, Bicep was introduced nationally in 1980. In 1997, atrazine was combined with S-metolachlor to produce Bicep II Magnum , since. S -metolachlor contains more of the active isomer and reduces the amount of herbicide needed for efficacy. 

Did not have survey data and were interpolated by the authors. aDinitroanilines Include trifluralin, pendimethalin, oryzalin, and ethalfluralin. bMetolachlor Includes S-metolachlor and metolachlor. 

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