Herbicides 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). 

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]. 

Enantioselective Hydrogenation of A -Arylimines in the Synthesis of the Chiral Herbicide, ( S)-Metolachlor... 

In Section 9-4-3, we mentioned that cationic Ir catalysts (sometimes called Crabtree catalysts) are quite active for hydrogenation of highly substituted C=C bonds. Moreover, asymmetric Ir-catalyzed hydrogenation of an imine is a key step in the industrial-scale synthesis of the herbicide (S)-metolachlor (Section 9-7-2). In addition to these applications, relatively recent work has shown that cationic Ir(I) complexes bonded to chiral ligands can catalyze asymmetric hydrogenation of unfunctionalized C=C bonds (i.e., C=C bonds to which no polar functional groups, such as C=0, are attached). 

Each year, Novartis manufactures wlOOOO tonnes of the the scheme below. The key to enantioselectivity is the first herbicide S-Metolachlor, the synthesis of which is shown in step of asymmetric hydrogenation. 

Particularly interesting are the industrial applications of catalytic systems based on these ligands. Thus, as the most illustrative example an enantioselective catalytic process for the large-scale production of the herbicide (S)-metolachlor has been developed (173,174). The key step is the asymmetric hydrogenation of an imine using an Ir/Xyliphos complex (Fig. 46). 

Following is a retrosynthetic analysis for the synthesis of the herbicide (S)-Metolachlor from 2-ethyl-6-methylaniline, chloroacetic acid, acetone, and methanol. 

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. 

Foy, C.L., J.S. Wilson, S. Mostaghimi, and R.W. Young (1989). Runoff losses of two triazine herbicides and metolachlor from conventional and no-till plots as influenced by sludge. Pestic. Terrest. Aquatic Environ. Proc., May 11-12, pp. 383-396. 

Herbicides. Herbicides are used in great quantities globally, accounting for over 15 billion in sales in 2001. A number of herbicides are produced as racemates and, as is the case for many pharmaceuticals, one enantiomer is often more potent than the other. Examples include Frontier, produced by BASF and Metolochlor, a Syngenta product. The active enantiomer, (S)-metolachlor, was introduced in 1999. BASF introduced Outlook , the S-enantiomer of Frontier, in 2001. 

With the exception of S-metolachlor, all the molecules listed under the column Final Target are used in pharmaceutical formulations. Dilitiazem is a Ca2+ antagonist, while Cilazapril is an angiotensin-converting enzyme inhibitor. Levofloxacin is an antibacterial, and cilastatin is used as an in vivo stabilizer of the antibiotic imipenem. S-metolachlor is a herbicide sold under the trade name of DUAL MAGNUM. Although the structures of the final targets are more complex than those of the intermediates, enantioselective syntheses of the intermediates are the most crucial steps in the complex synthetic schemes of these molecules. 

Gianessi et al. [7] therefore compared the amount of glyphosate that had been used on herbicide tolerant soybeans in 2001 to the amoimt of mixed herbicides that would be required to achieve the same degree of weed control. For each U.S. state, an alternative mix of herbicides was composed for comparison, based on the outcomes of a survey among experts, e.g. a mix of Boimdary (metribuzin s-metolachlor), Flexstar (fome-safen), and Select (clethodim) in Iowa (Table 1). 

S)-Metolachlor is the active ingredient of the herbicides Dual and Bicep, which are widely applied in the United States and were developed by the Swiss company Ciba-Geigy (now Novartis). The steric hindrance near the aryl-N bond restricts rotation about that bond. This restricted rotation results in a type of stereoisomerism called atropisomerism, resulting in aR and a,S configurations about the chiral aryl-N bond axis.113 There is also a stereogenic center (position /) on a carbon next to the N-atom in the amino side chain. All four possible stereoisomers of metolachlor are shown in Figure 9-3. 

Space limitations do not allow every procedure of importance to be mentioned, but one that should be included is the production process for (S)-metolachlor, a herbicide marketed under fhe trade name Dual Magnum by Syngenta (formerly Ciba-Geigy). Volume-wise, this presently constitutes fhe largest production process of any kind applying an asymmetric reaction, with its aimual capacity of more than 10000 tonnes [35]. The efficiency obtained in fhis method based on a planar... 

A remarkable increase in catalyst efficiency in SCCO2 as compared to conventional solvents was observed for the Ir-catalyzed enantioselective hydrogenation of imines shown in Scheme 12.12 [34]. Imine hydrogenation is a key step in the commercial synthesis of (S)-metolachlor, a commercial herbicide produced by Novartis in Switzerland. The reaction is approximately zero-order with respect to substrate in CO2 whereas it slows down dramatically at higher conversion in the organic solvent (Fig. 12.8). Thus, the time required for quantitative conversion is reduced by a factor of 20 when changing from the conventional to the supercritical solvent ... 

There are now numerous products that contain benoxacor and (S-)metolachlor, with and without further herbicide components (Table 5.2). As the patents for... 

The use of benoxacor with (S)-metolachlor is particularly necessary under stress conditions for maize. Injury to corn from (S)-metolachlor is greater under cool or wet soil conditions [6-8] where both the availability of the herbicide may be increased and the ability of maize to metabolize metolachlor reduced [9]. Benoxacor and metolachlor have similar chemical properties, influencing there behavior in soil, and this tends to ensure that the safener and herbicide are taken up together, hence providing safening under various weather conditions. 

From a historical perspective, the Monsanto process for the preparation of (l.)-DOPA in 1974 laid the foundation stone for industrial enantioselective catalysis. Since then it has been joined by a number of other asymmetric methods, such as enantioselective Sharpless epoxidation (glycidol (ARCO) and disparlure (Baker)), and cyclopropanation (cilastatin (Merck, Sumitomo) and pyre-throids (Sumitomo)). Nevertheless, besides the enantioselective hydrogenation of an imine for the production of (S)-metolachlor(a herbicide from Syngenta), the Takasago process for the production of (-)-menthol remains since 1984 as the largest worldwide industrial application of homogeneous asymmetric catalysis. [124]... 

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