Chiral pool technique

Clearly, there is a need for techniques which provide access to enantiomerically pure compounds. There are a number of methods by which this goal can be achieved . One can start from naturally occurring enantiomerically pure compounds (the chiral pool). Alternatively, racemic mixtures can be separated via kinetic resolutions or via conversion into diastereomers which can be separated by crystallisation. Finally, enantiomerically pure compounds can be obtained through asymmetric synthesis. One possibility is the use of chiral auxiliaries derived from the chiral pool. The most elegant metliod, however, is enantioselective catalysis. In this method only a catalytic quantity of enantiomerically pure material suffices to convert achiral starting materials into, ideally, enantiomerically pure products. This approach has found application in a large number of organic... 

Recently, chiral economic techniques have been developed which allow the complete transformation of a starting material into the desired enantiomer. According to a study by the market research firm of Frost and Sullivan, worldwide revenues due to chiral technology, which amounted to US 4.8 billion in 1999, will have reached more than triple the sum by 2009 — US 14.9 billion. One valuable approach is using the chiral pool as a large reservoir of optically pure building blocks, mainly derived from natural sources. 

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. 

There are many problems associated with carrying out asymmetric synthesis at scale. Many asymmetric transformations reported in the literature use the technique of low temperature to allow differentiation of the two possible diastereoisomeric reaction pathways. In some cases, the temperature requirements to see good asymmetric induction can be as low as -100°C. To obtain this temperature in a reactor is costly in terms of cooling and also presents problems associated with materials of construction and the removal of heat associated with the exotherm of the reaction itself. It is comforting to see that many asymmetric catalytic reactions do not require the use of low temperature. However, the small number of robust reactions often leads development chemists to resort to a few tried and tested approaches, namely chiral pool synthesis, use of a chiral auxiliary, or resolution. In addition, the scope and limitations associated with the use of a chiral catalyst often result in a less than optimal sequence either because the catalyst does not work well on the necessary substrate or the preparation of that substrate is long and costly. Thus, the availability of a number of different approaches helps to minimize these problems (Chapter 2). 

The same system also proven to be very efficient for the synthesis of 16, the glycosidic moiety of Altromycin B [26]. The method described by Kirschning proved to be the optimal oxidative method, giving quantitative yields without the requirement of any purification, whereas other oxidation techniques gave only mediocre results (Scheme 4.3). It was also the method of choice for the chiral-pool... 

A variety of established industrial processes for the manufacture of and new synthetic approaches to certain optically active compounds such as pharmaceuticals vitamins, and fine chemicals are surveyed. Among the techniques for obtaining optically pure intermediates covered in this review are classical or modified optical resolutions, the utilization of starting materials from the chiral pool, as well as stoichiometric and catalytic asymmetric transformations. 

Enantioseparations are intensively used as an access to intermediates and chiral pools of many synthetic methodologies for obtaining enantiomerically pure compounds. In addition, analytical enantioseparation is the most reliable instrumental technique that allows the estimation of the success of any enantioselective synthesis. Therefore, a chapter on this nonsynthetic topic hopefully can be of some use also for the readers of this volume, which comprises entirely synthetic topics. 

Direct separation of enantiomers by chromatography Use of covalent chiral auxiliaries Stereoselective synthesis of individual enantiomers Separation of diastereoisomers by physical techniques Synthesis from chirality pool materials... 

Of the three basic types of methodologies employed for the provision of chiral target molecules in optically enriched form, synthesis from chirality pool materials can often be the method of choice, providing that (i) suitable starting materials are readily available at reasonable cost, and (ii) it is not necessary to introduce extra steps which would otherwise be avoided, in, for example, the synthesis of an easily resolvable racemate. A distinct advantage of chirality pool synthesis over resolution techniques is the facility to correlate absolute configuration of the product with that of the starting material. 

Even the first thermotropic liquid crystals (cholesterol benzoate and cholesterol acetate) were chiral molecules, and their chiral mesophases were observed [2]. Here, the chirality is taken from the chiral pool. Because liquid crystals are needed in gram scales for physical research and technical applications, they should be prepared by short synthetic pathways using easily available starting materials. Thus, synthetic strategies based on the chiral pool are more often used than asymmetric synthesis or chiral separation techniques. 

Enantioselective catalysis is a very important technique in modem industrial chemistry, as is shown by the continuously increasing sales figures for enantiomerically pure substances. In 2003, chiral technology held a market share of 7.0 billion USD and was estimated to grow to 14.9 billion USD by the end of 2009. The estimated annual growth of conventional methods such as enantiomer separation or the use of chiral pools is 7%, whereas asymmetric synthetic methods are estimated to grow by 12% [1]. 

This technique uses starting materials that are themselves optically active and in the same orientation as the desired product. These are often naturally occurring compounds such as carbohydrates or L-amino acids. The biochemist will choose from this chiral pool . The synthetic route is designed to keep any intermediates and the final product formed in the same enantiomeric form. As a result, there is no need to carry out the costly separation process needed when a racemic mixture is produced. 

Having demonstrated the utility of the technique, the authors attempted a pooled approach in which five catalyst precursors were combined with the two chiral allylic esters at —78°G. The low temperature was necessary to avoid ligand scrambling, but the authors demonstrate that provided the molecular ion signals do not overlap, ESI-MS can be used very effectively to screen pooled catalysts. 

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