Drugs asymmetric synthesis

Hydroxylation of sodium and potassium enolates side reaction with lithium Substrate controlled stereoselectivity asymmetric hydroxylation Asymmetric hydroxylation with camphor sultam derivatives Asymmetric synthesis of tetracycline precursors Synthesis of a calcium channel opening drug Asymmetric synthesis ofbuproprion Summary... 

Asymmetric synthesis is a stimulating academic challenge, but since it has become clear that most chiral drugs can be administered safely only in the enantiomerically pure form, the industrial need for asymmetric methods has made research in asymmetric synthesis absolutely necessary [5]. This has driven a renaissance in the discipline of organic chemistry, because all of the old-established reactions need to be reinvestigated for their application in asymmetric synthesis [6]. This has also applied... 

Although very efficient, the broad application of the direct preparation is restricted due to the limited number of pure starting enantiomers. The design of a multistep process that includes asymmetric synthesis is cumbersome and the development costs may be quite high. This approach is likely best suited for the multi-ton scale production of commodity enantiomers such as the drugs ibuprofen, naproxen, atenolol, and albuterol. However, even the best asymmetric syntheses do not lead to products in an enantiomerically pure state (100 % enantiomeric excess). Typically, the product is enriched to a certain degree with one enantiomer. Therefore, an additional purification step may be needed to achieve the required enantiopurity. 

A different approach to making chiral drugs is asymmetric synthesis. An optically inactive precursor is converted to the drug by a reaction that uses a special catalyst, usually an enzyme (Chapter 11). If all goes well, the product is a single enantiomer with the desired physiological effect In 2001, William S. Knowles, Ryogi Noyori, and K. Barry Sharpless won the Nobel Prize in chemistry for work in this area. 

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. 

We have developed the efficient synthesis of the SERM drug candidate 1 and successfully demonstrated the process on a multiple kilogram scale to support the drug development program. A novel sulfoxide-directed borane reduction of vinyl sulfoxides was discovered. The mechanistic details of this novel reaction were explored and a plausible mechanism proposed. The sequence of asymmetric oxidation of vinyl sulfoxides followed by stereospecific borane reduction to make chiral dihydro-1,4-benzoxathiins was applied to the asymmetric synthesis of a number of other dihydro-1,4-benzoxathiins including the sweetening agent 67. 

This chapter has introduced the aldol and related allylation reactions of carbonyl compounds, the allylation of imine compounds, and Mannich-type reactions. Double asymmetric synthesis creates two chiral centers in one step and is regarded as one of the most efficient synthetic strategies in organic synthesis. The aldol and related reactions discussed in this chapter are very important reactions in organic synthesis because the reaction products constitute the backbone of many important antibiotics, anticancer drugs, and other bioactive molecules. Indeed, study of the aldol reaction is still actively pursued in order to improve reaction conditions, enhance stereoselectivity, and widen the scope of applicability of this type of reaction. 

Chapter 2 to 6 have introduced a variety of reactions such as asymmetric C-C bond formations (Chapters 2, 3, and 5), asymmetric oxidation reactions (Chapter 4), and asymmetric reduction reactions (Chapter 6). Such asymmetric reactions have been applied in several industrial processes, such as the asymmetric synthesis of l-DOPA, a drug for the treatment of Parkinson s disease, via Rh(DIPAMP)-catalyzed hydrogenation (Monsanto) the asymmetric synthesis of the cyclopropane component of cilastatin using a copper complex-catalyzed asymmetric cyclopropanation reaction (Sumitomo) and the industrial synthesis of menthol and citronellal through asymmetric isomerization of enamines and asymmetric hydrogenation reactions (Takasago). Now, the side chain of taxol can also be synthesized by several asymmetric approaches. 

A classical example is the development of soluble chiral catalysts for homogenous asymmetric hydrogenation. The story began with the discovery of Wilkinson s catalyst [4]. In 1968, Horner [5] and Knowles [6], independently, reported the feasibility of asymmetric hydrogenations in the presence of optically active Wilkinson-type catalyst. Although the optical yields were rather low, further studies in this direction were the basis of the success of Monsanto s asymmetric synthesis of the anti-Parkinson s drug L-DOPA. The key steps of the synthesis are outlined in Scheme 11.1. 

Before an asymmetric synthesis appeared of levofloxacin (1, (—)-ofloxacin), (—)- ofloxacin was isolated via optical, enzymatic, and crystallization resolution of the racemic ofloxacin (17) Drugs Future, 1992 Hayakawa et al., 1986, 1991). For instance, tricyclic core 52 was converted to ( + )-3,5-dinitrobenzoyl derivative 54 in 75% yield (Scheme 4.5). The enantiomers were then separated via high-performance liquid chromatography (HPLC) with a SUMIPAX OA-4200 column to deliver optically pure benzoyl esters 55a and 55b (Drugs Future, 1992 Hayakawa et al., 1986, 1991). 

Captopril (1), an approved antihypertensive drug, was prepared from (S)-proline. The key step in an elegant asymmetric synthesis of (1) was a hydrogenation of (50) to give (51) which is hydrolyzed to afford (1) 8S). 

Hauck, R.-S. and Nau, H. (1996) Asymmetric synthesis and enantioselective teratogenicity of 2-n-propyl-4-pentenoic acid (4-ene-VPA), an active metabolite of the anticonvulsant drug, valproic acid. Toxicol. Lett. 49 41-48. 

Around 70% of the pharmaceuticals on the market are chiral, and approximately one third of these are chiral amines [1], This represents a substantial number of achve drug substances that are typically manufactured at a scale of 1-100 l y . The three main manufacturing processes used to introduce these homochiral centers are from optically active starting materials (the so-called Chiral Pool approach), by asymmetric synthesis and by resolution. The last technique is widely practiced but results in waste of the undesired enantiomer. This chapter deals with developments in asymmetric transformations, that is to say methods for augmenting the yield of amine resolution processes to theory 100%, resulting in an alternative to asymmetric synthesis and a practical Green Chemistry solution to the synthesis of optically active amines. Figure 13.1 shows different approaches to the asymmetric transformation that will be discussed in the chapter. 

The first edition of Catalytic Asymmetric Synthesis, published in the fall of 1993, was very warmly received by research communities in academia and industries from graduate students, research associates, faculty, staff, senior researchers, and others. The book was published at the very moment that the Food Drug Administration (FDA) in the United States clarified the situation in Chiral Drugs, the word chirotechnology was created, and chirotechnology industries were spawning in the United States and Britain. 

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