Asymmetric epoxidation drug synthesis

Senanayake, C. H., Jacobsen, E. N. Chiral (Salen)Mn(III) Complexes in Asymmetric Epoxidations Practical Synthesis of Ci s - Am i n o i n d ano 1 and Its Application to Enantiopure Drug Synthesis, Process Chemistry in the Pharmaceutical Industry, Gadamasetti, K. G. Marcel Dekker New York, 1999, Chapter 18, 327. 

The asymmetric hydrogenation of cinnamic acid derivatives has been developed by Knowles at Monsanto [4], The synthesis of L-dopa (Figure 4.3), a drug for the treatment of Parkinson s disease, has been developed and is applied on an industrial scale. Knowles received the Nobel Prize for Chemistry in 2001 together with Noyori (see below, BINAP ) and Sharpless (asymmetric epoxidation). 

Take the millions of lives saved by the synthesis of indinavir, for example. This drug would not have been possible had not the Sharpless and Jacobsen asymmetric epoxidations, the catalytic asymmetric reduction, and the stereoselective enolate alkylation, along with many of the methods tried but not used in the final synthesis, been invented and developed by organic chemists in academic and industrial research laboratories. Some of the more famous names involved, like Sharpless, Jacobsen, and Noyori, invented new methods, while others modified and optimized those methods, and still others applied the methods to new types of molecules. Yet all built on the work of other chemists. 

Examples of Pharmaceutical Product Synthesis In this section, a couple of examples concerning the application of the Mn(salen) asymmetric epoxidation method are described, focusing on cis substituted alkenes as intermediate substrates that are selectively oxidized by this catalytic system. Other examples of application of Mn(salen) on different classes of alkenes for the synthesis of drugs are reported in a recent review paper. ... 

As an application of the modified conditions, the asymmetric synthesis of (7 )-fiuoxetine was demonstrated (Scheme 35.28). Fluoxetine is an antidepressant drug and currently marketed as a racemate. Asymmetric epoxidation of amide 101 under Shibasaki s conditions provided epoxide 102 in 91% yield and 99% ee. Subsequent regionselec-tive reduction with Red-Al in the presence of a crown ether afforded the (3-hydoxyl amide 103, which was converted into (/ )-fluoxetine 104 in two steps. °... 

The asymmetric oxidation of indene to the corresponding epoxide (Equation 24) is carried out commercially by Sepracor on a small scale. Chiral indene oxide is an intermediate in the synthesis of crixivan (an HIV protease inhibitor). Reaction is carried out at 5°C with moderately high turnover numbers in the presence of an exotic donor ligand ( P3NO , 3-phenylpropylpyridine N oxide) and sodium hypochlorite as the terminal oxidant. A similar epoxidation of a simple cis olefin (Equation 25) leads to an enantiomerically pure amino-alcohol used in the synthesis of taxol, a potent anticancer drug. 

Besides the more common reactions such as hydrogenation, isomerization, alkylation, and the Diels-Alder reaction. Sharpless epoxidation and dihydroxylation by asymmetrical catalysis are rapidly emerging as reactions with immense industrial potential. Table 9.7 lists some important syntheses based on asymmetric catalysis. These include processes for the pharmaceutical drugs (S)-naproxen, (S)-ibuprofen, (,S)-propranolol, L-dopa, and cilastatin, a fragrance chemical, L-menthol, and an insecticide (/ )-disparlure. Deltamethrin, an insecticide, is another very good example of industrial asymmetric synthesis. The total synthetic scheme is also given for each product. In general, the asymmetric step is the key step in the total synthesis, but this is not always so, as in the production of ibuprofen. Many of the processes listed in the table are in industrial production. 

Styrene epoxide is a valuable building block and is used in the production of the antihelmintic drug Levamisole. The styrene epoxide for the synthesis of drugs must be enantiopure. There are some chemical asymmetric synthetic routes but the yields are only in the range 45-50%. 

The trifluoromethyl epoxide 150 is an important intermediate in the synthesis of the anti-inflammatory drug lead BI-115 (17, Scheme 2.24). Researchers at Boehringer Ingelheim developed an efficient protocol for the synthesis of the a-trifluoromethyl-a-alkyl epoxide 150 that involved use of (lR,2S)-trans-2-phenylcy-clohexanol 146 as a chiral auxiliary for the asymmetric addition of a trifluoromethyl anion to the a-keto ester 147 153 synthesis of 150 initiated with the esterification of the a-keto acid 145 with (lR,2S)-trans-2-... 

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