Enantiopure compound

Diastereomeric derivathation of a chiral alcohol (111) with an enantiopure compound such as Mosher s reagent [20445-33-4] (a-ttifluoromethyl-a-methoxy-a-phenylacetjichloride) (112) (91) results in two distinct compounds (113) and (114) with nonequivalent chemical shifts in the H-nmr spectmm (92). 

From a historical perspective it is interesting to note that the Nozaki experiment was, in fact, a mechanistic probe to establish the intermediacy of a copper carbe-noid complex rather than an attempt to make enantiopure compounds for synthetic purposes. To achieve synthetically useful selectivities would require an extensive exploration of metals, ligands and reaction conditions along with a deeper understanding of the reaction mechanism. Modern methods for asymmetric cyclopropanation now encompass the use of countless metal complexes [2], but for the most part, the importance of diazoacetates as the carbenoid precursors still dominates the design of new catalytic systems. Highly effective catalysts developed in... 

Despite the still growing number of available methods for the preparation of enantiopure compounds by the use ofasymmetric catalysis, kinetic resolution (KR) is still the most employed method in the industry [4], and in most cases biocatalysts (enzymes) are used. 

Catalytic transformation based on combined enzyme and metal catalysis is described as a new class of methodology for the synthesis of enantiopure compounds. This approach is particularly useful for dynamic kinetic resolution in which enzymatic resolution is coupled with metal-catalyzed racemization for the conversion of a racemic substrate to a single enantiomeric product. 

Hydrogen transfer reactions are reversible, and recently this has been exploited extensively in racemization reactions in combination with kinetic resolutions of racemic alcohols. This resulted in dynamic kinetic resolutions, kinetic resolutions of 100% yield of the desired enantiopure compound [30]. The kinetic resolution is typically performed with an enzyme that converts one of the enantiomers of the racemic substrate and a hydrogen transfer catalyst that racemizes the remaining substrate (see also Scheme 20.31). Some 80 years after the first reports on transfer hydrogenations, these processes are well established in synthesis and are employed in ever-new fields of chemistry. 

In the contemporary production of enantiopure compounds this feature is highly appreciated. Currently, kinetic resolution of racemates is the most important method for the industrial production of enantiomerically pure compounds. This procedure is based on chiral catalysts or enzymes, which catalyze conversion of the enantiomers at different rates. The theoretical yield of this type of reaction is only 50%, because the unwanted enantiomer is discarded. This generates a huge waste stream, and is an undesirable situation from both environmental and economic points of view. Efficient racemization catalysts that enable recycling of the undesired enantiomer are, therefore, of great importance. 

IV-functionalised OZTs being enantiopure compounds can be seen as important tools in asymmetric synthesis. 

Dynamic kinetic resolution (DKR) is an attractive protocol for the production of enantiopure compounds from racemic mixtures [45]. The concept of DKR is illustrated in Scheme 5.13. In many cases, DKRs are accomplished by the combination of enzymatic resolution and transition-metal-catalyzed racemization based on hydrogen transfer. Thus, the use of Cp Ir complexes as catalysts for racemization in DKR can be anticipated. 

Since the early times of stereochemistry, the phenomena related to chirality ( dis-symetrie moleculaire, as originally stated by Pasteur) have been treated or referred to as enantiomericaUy pure compounds. For a long time the measurement of specific rotations has been the only tool to evaluate the enantiomer distribution of an enantioimpure sample hence the expressions optical purity and optical antipodes. The usefulness of chiral assistance (natural products, circularly polarized light, etc.) for the preparation of optically active compounds, by either resolution or asymmetric synthesis, has been recognized by Pasteur, Le Bel, and van t Hoff. The first chiral auxiliaries selected for asymmetric synthesis were alkaloids such as quinine or some terpenes. Natural products with several asymmetric centers are usually enantiopure or close to 100% ee. With the necessity to devise new routes to enantiopure compounds, many simple or complex auxiliaries have been prepared from natural products or from resolved materials. Often the authors tried to get the highest enantiomeric excess values possible for the chiral auxiliaries before using them for asymmetric reactions. When a chiral reagent or catalyst could not be prepared enantiomericaUy pure, the enantiomeric excess (ee) of the product was assumed to be a minimum value or was corrected by the ee of the chiral auxiliary. The experimental data measured by polarimetry or spectroscopic methods are conveniently expressed by enantiomeric excess and enantiomeric... 

What happens for a nonracemic mixture of enantiomers Is it possible to calculate the values of the chiral properties of the solution from knowledge of the properties of the enantiopure compound In principle, yes, on the condition that there is no autoassociation or aggregation in solution. Then, the observed properties will be simply the weighted combination of the properties of two enantiomers. A nice example of where this normal law may be broken was discovered by Horeau in 1967 it is the nonequivalence between enantiomeric excess (ee) and optical purity (op, with op = [a]exi/[ ]max) for 2,2-methylethyl-succinic acid. In chloroform op is inferior to ee, while in methanol op = ee. This was explained by the formation of diastereomeric aggregates in chloroform, while the solvation by methanol suppresses the autoassociation. 

We have demonstrated the enantioselective synthesis of near-enantiopure compounds by asymmetric photodegradation of racemic pyrimidyl alkanol 2c by circularly polarized light followed by asymmetric autocatalysis. This is the first example of asymmetric autocatalysis triggered directly by a chiral physical factor CPL. 

A major reason why synthetic chemists have become interested in biological methods as mentioned above, is that biocatalysis shows selectivity and specificity in catalysis. This interest in turn is mainly due to the need to synthesise enantiopure compounds as chiral building blocks for dmgs and agrochemicals. 

Figure 2.2 Production of enantiopure compounds using hydrolytic enzymes. In (a) a prochiral diester is hydrolysed to yield predominance (in theory 100%) of one enantiomer. In the next example (b) a raeso-diester is hydrolysed to yield predominance (in theory 100%) of one enantiomer of the monoester. If kj>k2 the (IS, 2i )-enantiomer is formed to the greatest extent. Due to the preference of the enzyme k4>kj and the lower monoester (IR, 2S) will be removed fastest. Hence both steps will lead to an increase of the upper enantiomer at the monoester stage. If the reaction proceeds to completion, however, the result will be another raeio-compound, a diol. In example (c) a racemic secondary ester is resolved by hydrolysis. One monoester is hydrolysed faster than the other and this leads to kinetic resolution.

As discussed in part 2.2.3 biocatalysis may be used both in asymmetric synthesis and resolution in order to obtain enantiopure compounds. A major difference between asymmetric synthesis and resolution is that the former in theory may give 100% yield of the wanted enantiomer. Resolution on the other hand can only give 50% yield since the starting point is a mixture of 50% of each enantiomer. This is the classical disadvantage of resolution. 

The second aspect has already been addressed in relation to the term EPC synthesis. The meaning of the term enantiomerically pure compound is self-evident, i.e., a compound which consists only of superimposable chiral molecules. Unfortunately, such a compound is not likely to exist except as a concept. Realistically, the label pure, hence enantiomerically pure, can only be given according to the analytical tools available or applied. Thus, two terms are required one to describe the abstract concept, enantiomerically pure as defined above, the other to describe a real compound, as enantiopure according to the available or applied analytical methods. The term enantiopure has already been used by the Fluka Chemical Company, and was also recommended in one of the letters mentioned previously20. One consequence of this distinction is a re-interpretation of the term EPC synthesis to mean enantiopure compound synthesis. 

Hence, when enantiopure compounds are needed, desymmetrization constitutes a useful alternative to kinetic resolution of racemates. Hydrolases are useful for such transformations, in both hydrolytic and acylation reactions [6]. Meso-compounds have been used extensively in such reactions. The success of such a reaction depends on one of the pro-R or pro-S groups reacting much faster than the other. If the monoderivatized product reacts further, the second step of course gives the doubly reacted meso-product. If the second step favors the minor one of... 

It should be mentioned that the great majority of dynamic kinetic resolutions reported so far are carried out in organic solvents, whereas all cyclic deracemizations are conducted in aqueous media. Therefore, formally, this latter methodology would not fit the scope of this book, which is focused on the synthetic uses of enzymes in non-aqueous media. However, to fully present and discuss the applications and potentials of chemoenzymatic deracemization processes for the synthesis of enantiopure compounds, chemoenzymatic cyclic de-racemizations will also be briefly treated in this chapter, as well as a small number of other examples of enzymatic DKR performed in water. 

Recent interest in the preparation of enantiopure compounds both in the laboratory and on an industrial scale has created the need for new synthetic methodologies... 

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