Pyrethroids enantioselective synthesis

Scheme 5.5 Hevea brasiliensis HNL catalyzes a key step in the enantioselective synthesis of pyrethroid insecticides.

Enantioselection can be controlled much more effectively with the appropriate chiral copper, rhodium, and cobalt catalyst.The first major breakthrough in this area was achieved by copper complexes with chiral salicylaldimine ligands that were obtained from salicylaldehyde and amino alcohols derived from a-amino acids (Aratani catalysts ). With bulky diazo esters, both the diastereoselectivity (transicis ratio) and the enantioselectivity can be increased. These facts have been used, inter alia, for the diastereo- and enantioselective synthesis of chrysan-themic and permethrinic acids which are components of pyrethroid insecticides (Table 10). 0-Trimethylsilyl enols can also be cyclopropanated enantioselectively with alkyl diazoacetates in the presence of Aratani catalysts. In detailed studies,the influence of various parameters, such as metal ligands in the catalyst, catalyst concentration, solvent, and alkene structure, on the enantioselectivity has been recorded. Enantiomeric excesses of up to 88% were obtained with catalyst 7 (R = Bz = 2-MeOCgH4). 

When the carbinol substituents (R) were the bulky 5-ler -butyl-2-(n-octyloxy)phenyl group, optimum enantioselectivities were achieved with the catalytic use of the corresponding Cu(II) complex (2) in both enantiomeric forms. Specific applications of the Aratani catalysts have included the synthesis of chrysanthemic acid esters (Eq. 5.6) and a precursor to permethrinic acid, both potent units of pyrethroid insecticides, and for the commercial preparation of ethyl (S)-2,2-dimethylcyclopropanecarboxylate (Eq. 5.2), which is used for constructing cilastatin. Several other uses of these catalysts and their derivatives for cyclopropanation reactions have been reported albeit, in most cases, with only moderate enantioselectivities [26-29],... 

We chose to explore the intramolecular alkylation of amide enolates as a potential stereoselective route to cis pyrethroid cyclopropane carboxylates. If the relationship between the stereoselection in enolate formation and ring closure is operable, amide enolates would be an excellent means of developing a stereoselective synthesis of cis products (8). Furthermore, recent progress in achieving enantioselection in the intermolecular alkylation of chiral amide enolates would provide a means of obtaining optically active pyrethroid acids (Figure 6) (9-13). 

In this way, esters of chrysanthemic acid (2) [15,16,18] and permethrinic acid [17,18], which are important precursors for the synthesis of pyrethroid insecticides, can be prepared in >90% ee. Although enantioselective cyclopropanation cannot compete with conventional industrial syntheses of optically active pyrethroids, a technical process for the cyclopropanation of 2-methylpropene was successfully implemented at Sumitomo [18]. The product, ethyl (-l-)-2,2-dimeth-ylcyclopropanecarboxylate, serves as a starting material for the production of cilastatin, a dehydropeptidase inhibitor used as a drug to suppress the degradation of the P-lactam antibiotic iminipenem. 

The synthesis of cllastatin constitutes one of the first enantioselective syntheses on an Industrial scale. In 1966, H. NozakI and R. Noyorl Investigated the enantioselective [2 -I-1 ]-cycloaddition of diazo-acetic esters to olefins. From this, Sumitomo developed industrial processes for the preparation of pyrethroids and cilastatin. In the key step, ethyl diazoacetate is decomposed in presence of isobutene at a dimeric, enantio-merically pure copper complex. The resulting ethyl di-methylcyclopropanecarboxyl-ate has an optical purity of 92% ee. 

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