Энантиоселективный синтез: получение хиральных соединений с высокой стереоселективностью.

Chemical reaction(s) which favor one chiral isomer over another

Enantioselective synthesis, also called asymmetric synthesis, is a form of chemical synthesis. It is defined by IUPAC as "a chemical reaction (or reaction sequence) in which one or more new elements of chirality are formed in a substrate molecule and which produces the stereoisomeric (enantiomeric or diastereomeric) products in unequal amounts." Put more simply: it is the synthesis of a compound by a method that favors the formation of a specific enantiomer or diastereomer. Enantiomers are stereoisomers that have opposite configurations at every chiral center. Diastereomers are stereoisomers that differ at one or more chiral centers. Enantioselective synthesis is a key process in modern chemistry and is particularly important in the field of pharmaceuticals, as the different enantiomers or diastereomers of a molecule often have different biological activity.

Enantioselective catalysis (known traditionally as "asymmetric catalysis") is performed using chiral catalysts, which are typically chiral coordination complexes. Catalysis is effective for a broader range of transformations than any other method of enantioselective synthesis. The chiral metal catalysts are almost invariably rendered chiral by using chiral ligands, but it is possible to generate chiral at metal complexes composed entirely of achiral ligands. Most enantioselective catalysts are effective at low substrate/catalyst ratios. Given their high efficiencies, they are often suitable for industrial scale synthesis, even with expensive catalysts. A versatile example of enantioselective synthesis is asymmetric hydrogenation, which is used to reduce a wide variety of functional groups. The design of new catalysts is dominated by the development of new classes of ligands. Certain ligands, often referred to as "privileged ligands", are effective in a wide range of reactions; examples include BINOL, Salen, and BOX. Most catalysts are effective for only one type of asymmetric reaction. For example, Noyori asymmetric hydrogenation with BINAP/Ru requires a β ketone, although another catalyst, BINAP/diamine Ru, widens the scope to α,β alkenes and aromatic chemicals.

A chiral auxiliary is an organic compound which couples to the starting material to form a new compound which can then undergo diastereoselective reactions via intramolecular asymmetric induction. At the end of the reaction the auxiliary is removed, under conditions that will not cause racemization of the product. It is typically then recovered for future use. Chiral auxiliaries must be used in stoichiometric amounts to be effective and require additional synthetic steps to append and remove the auxiliary. However, in some cases the only available stereoselective methodology relies on chiral auxiliaries and these reactions tend to be versatile and very well studied, allowing the most time efficient access to enantiomerically pure products. The advantages of these reagents include very high e. e. s and reagent specificity, as well as mild operating conditions and low environmental impact. Biocatalysts are more commonly used in industry than in academic research; for example in the production of statins. The high reagent specificity can be a problem, however, as it often requires that a wide range of biocatalysts be screened before an effective reagent is found.

Chiral pool synthesis is one of the simplest and oldest approaches for enantioselective synthesis. A readily available chiral starting material is manipulated through successive reactions, often using achiral reagents, to obtain the desired target molecule. This can meet the criteria for enantioselective synthesis when a new chiral species is created, such as in an SN2 reaction. Chiral pool synthesis is especially attractive for target molecules having similar chirality to a relatively inexpensive naturally occurring building block such as a sugar or amino acid. However, the number of possible reactions the molecule can undergo is restricted and tortuous synthetic routes may be required (e. g. Oseltamivir total synthesis). This approach also requires a stoichiometric amount of the enantiopure starting material, which can be expensive if it is not naturally occurring.

The two enantiomers of a molecule possess many of the same physical properties (e. g. melting point, boiling point, polarity etc.) and so behave identically to each other. As a result, they will migrate with an identical Rf in thin layer chromatography and have identical retention times in HPLC and GC. Their NMR and IR spectra are identical. This can make it very difficult to determine whether a process has produced a single enantiomer (and crucially which enantiomer it is) as well as making it hard to separate enantiomers from a reaction which has not been 100% enantioselective. Fortunately, enantiomers behave differently in the presence of other chiral materials and this can be exploited to allow their separation and analysis. Enantiomers do not migrate identically on chiral chromatographic media, such as quartz or standard media that has been chirally modified. This forms the basis of chiral column chromatography, which can be used on a small scale to allow analysis via GC and HPLC, or on a large scale to separate chirally impure materials. However this process can require large amount of chiral packing material which can be expensive. A common alternative is to use a chiral derivatizing agent to convert the enantiomers into a diastereomers, in much the same way as chiral auxiliaries. These have different physical properties and hence can be separated and analysed using conventional methods. Special chiral derivitizing agents known as 'chiral resolution agents' are used in the NMR spectroscopy of stereoisomers, these typically involve coordination to chiral europium complexes such as Eu(fod)3 and Eu(hfc)3. The separation and analysis of component enantiomers of a racemic drugs or pharmaceutical substances are referred to as chiral analysis. or enantioselective analysis. The most frequently employed technique to carry out chiral analysis involves separation science procedures, specifically chiral chromatographic methods. The enantiomeric excess of a substance can also be determined using certain optical methods. The oldest method for doing this is to use a polarimeter to compare the level of optical rotation in the product against a 'standard' of known composition. It is also possible to perform ultraviolet visible spectroscopy of stereoisomers by exploiting the Cotton effect. One of the most accurate ways of determining the chirality of compound is to determine its absolute configuration by X ray crystallography. However this is a labour intensive process which requires that a suitable single crystal be grown.

The development of enantioselective synthesis was initially slow, largely due to the limited range of techniques available for their separation and analysis. Diastereomers possess different physical properties, allowing separation by conventional means, however at the time enantiomers could only be separated by spontaneous resolution (where enantiomers separate upon crystallisation) or kinetic resolution (where one enantiomer is selectively destroyed). The only tool for analysing enantiomers was optical activity using a polarimeter, a method which provides no structural data. It was not until the 1950s that major progress really began. Driven in part by chemists such as R. B. Woodward and Vladimir Prelog but also by the development of new techniques. The first of these was X ray crystallography, which was used to determine the absolute configuration of an organic compound by Johannes Bijvoet in 1951. Chiral chromatography was introduced a year later by Dalgliesh, who used paper chromatography to separate chiral amino acids. Although Dalgliesh was not the first to observe such separations, he correctly attributed the separation of enantiomers to differential retention by the chiral cellulose. This was expanded upon in 1960, when Klem and Reed first reported the use of chirally modified silica gel for chiral HPLC separation.

While it was known that the different enantiomers of a drug could have different activities, with significant early work being done by Arthur Robertson Cushny, this was not accounted for in early drug design and testing. However, following the thalidomide disaster the development and licensing of drugs changed dramatically. First synthesized in 1953, thalidomide was widely prescribed for morning sickness from 1957 to 1962, but was soon found to be seriously teratogenic, eventually causing birth defects in more than 10,000 babies. The disaster prompted many countries to introduce tougher rules for the testing and licensing of drugs, such as the Kefauver Harris Amendment (US) and Directive 65/65/EEC1 (EU). Early research into the teratogenic mechanism, using mice, suggested that one enantiomer of thalidomide was teratogenic while the other possessed all the therapeutic activity. This theory was later shown to be incorrect and has now been superseded by a body of research. However it raised the importance of chirality in drug design, leading to increased research into enantioselective synthesis.