Optically active compounds synthesis

R. A. Sheldon, Chirotechnology Industrial Synthesis of Optically Active Compounds, Marcel Dekker, Inc., New York, 1993. 

In a catalytic asymmetric reaction, a small amount of an enantio-merically pure catalyst, either an enzyme or a synthetic, soluble transition metal complex, is used to produce large quantities of an optically active compound from a precursor that may be chiral or achiral. In recent years, synthetic chemists have developed numerous catalytic asymmetric reaction processes that transform prochiral substrates into chiral products with impressive margins of enantio-selectivity, feats that were once the exclusive domain of enzymes.56 These developments have had an enormous impact on academic and industrial organic synthesis. In the pharmaceutical industry, where there is a great emphasis on the production of enantiomeri-cally pure compounds, effective catalytic asymmetric reactions are particularly valuable because one molecule of an enantiomerically pure catalyst can, in principle, direct the stereoselective formation of millions of chiral product molecules. Such reactions are thus highly productive and economical, and, when applicable, they make the wasteful practice of racemate resolution obsolete. 

In general, yields of (/ )-acyloins and (2S,3/ )-diols, respectively, are low due to the formation of several byproducts (mainly reduction products of the substrate). Nevertheless, the optically active compounds thus obtained are extremely useful intermediates for the synthesis of many natural products51. 

The enantioselective 1,4-addition addition of organometaUic reagents to a,p-unsaturated carbonyl compounds, the so-called Michael reaction, provides a powerful method for the synthesis of optically active compounds by carbon-carbon bond formation [129]. Therefore, symmetrical and unsymmetrical MiniPHOS phosphines were used for in situ preparation of copper-catalysts, and employed in an optimization study on Cu(I)-catalyzed Michael reactions of di-ethylzinc to a, -unsaturated ketones (Scheme 31) [29,30]. In most cases, complete conversion and good enantioselectivity were obtained and no 1,2-addition product was detected, showing complete regioselectivity. Of interest, the enantioselectivity observed using Cu(I) directly in place of Cu(II) allowed enhanced enantioselectivity, implying that the chiral environment of the Cu(I) complex produced by in situ reduction of Cu(II) may be less selective than the one with preformed Cu(I). 

The synthesis of the first optically active compound is illustrated in Eq. (16) it was obtained with retention (>85%) of configuration about silicon 223). 

The synthesis of optically active compounds by the diastereoselective reaction of allyltitanium reagents with chiral electrophiles has also been reported. The reaction of allyltitanium reagents with chiral imines proceeds with excellent diastereoselectivity, as shown in Eq. 9.28, thus providing a new method for synthesizing optically active homoallylic amines with or without a P-substituent [51,52],... 

There are two possible approaches for the preparation of optically active products by chemical transformation of optically inactive starting materials kinetic resolution and asymmetric synthesis [44,87], For both types of reactions there is one principle in order to make an optically active compound we need another optically active compound. A kinetic resolution depends on the fact that two enantiomers of a racemate react at different rates with a chiral reagent or catalyst. Accordingly, an asymmetric synthesis involves the creation of an asymmetric center that occurs by chiral discrimination of equivalent groups in an achiral starting material. This can be done either by enan-tioselective (which involves the reaction of a prochiral molecule with a chiral substance) or diastereoselective (which involves the preferential formation of a single diastereomer by the creation of a new asymmetric center in a chiral molecule) synthesis. 

Therefore, as we have seen, we can not prepare an optically active compound from an inactive one by the ordinary laboratory methods. Such a synthesis however, can be accomplished by attaching an optically active molecule or groups to the original compound and then removing it after the new asymmetric atom has been produced. 

The asymmetric synthesis thus carried out is also known as partial asymmetric synthesis and to distinguish it from that where no optically active compound is used but in its place circularly polarized light is used, we use the term absolute asymmetric synthesis. 

In addition to sulfimides, the nitrogen analogs of sulfinates and sulfinamides are chiral and have been obtained as optically active compounds. For instance, the synthesis of diastereomeric menthyl p-toluenesulfinimidoates 90 mentioned above was effected by Cram and his collaborators (18,137) on two ways. The first comprised the reaction of racemic A -tosyl-p-tolueneiminosulfinyl chloride 92 with menthol, followed by separation of the diastereomers of 90, whereas in the second method the reaction of the ester (->45 with chloramine T was utilized. 

Many reactions may be successfully utilized in the synthesis of compounds with sigma bonds between group IV3 metals and transition metals, but none is of general applicability. Moreover, the problem is complicated in the case of optically active compounds since ... 

Sugars are often used as chiral precursors for the synthesis of optically active compounds, because they are readily available in large quantities and they are relatively inexpensive. The major restriction is that only the D-se-ries of sugars is usually available. An exception is arabinose, which is an attractive chiral source since both enantiomers are commercially available. 

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... 

Sheldon RA (1993) Chirotechnology industrial synthesis of optically active compounds. Marcel Dekker, New York Basel Hong Kong... 

The synthesis of 2-(trifluoromethyl) derivatives is more difficult and the compound preferentially obtained depends on the substituents and on the reaction conditions. Thus, the reaction of tryptophan with TFAA gives the 5(47/)-oxazolone without racemization." However, when this optically active product is dissolved in acetonitrile the racemic 5(47/)-oxazolone is obtained. On the other hand, treatment of the optically active compound with hot aqueous dioxane gave the isomeric 5(27/)-oxazolone (see Scheme 7.2). 

The potential of lyases for the synthesis of optically active compounds are of commercial interest, because these enzymes are stereospecific and do not require complicated cofactor recycling procedures. What types of reactions are catalyzed by lyases Lyases typically catalyze reversible reactions. How can you push the equilibrium in the desired direction ... 

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