Optically active compounds discovery

Many resolving agents derived from natural products have been used since the first discovery of the process, and they are still effective. Many examples are described in the literature.17,18 Synthetic resolving agents, such as a-methylbenzylamine, l-phenyl-2-(p-tolyl)ethylamine, and mandelic acid are very important ones, and widely used for the production of various optically active compounds. 

M. K. O Brien and B. Vanase, Curr. Opin. Drug Discovery Dev., 3,793-806 (2000) R. A Sheldon, Ed., Chirotechnology Industrial Synthesis of Optically Active Compounds, Marcel Dekker, New York, 1993. 

For development of a new chemical entity, the resolution of an optically active compound should be available in an earlier stage of the discovery process of the preformulation study. Selection of the enantiopure component or racemic mixtures to be a market product must be decided before patent application and IND submission. Heavy investment in the wrong chiral compounds may be lost if another enantiomer is to be developed. 

Racemic acid is of considerable historical interest as it was the first inactive substance to be resolved into optically active compounds. The remarkable discovery was made by Pasteur in 1848 in an investigation of the crystalline structure of the salts of racemic acid. It was found that two kinds of crystals, which differed slightly in the relative position of the faces they contained, were formed when a solution of the sodium ammonium salt of racemic acid was allowed to crystallize spontaneously. The relation in form which the two kinds of crystals bear to each other, is that of an object and its reflection in a mirror. Pasteur separated the two kinds of crystals and examined the solutions of each in polarized light. He found that one solution was dextro-rotatory and the other was levo-rotatory. From the two salts two acids were isolated one was ordinary d-tartaric acid, the other a new acid which was levo-rotatory. When equal weights of the two acids were mixed and recrystallized, inactive racemic acid was obtained. 

New catalytic systems are being continually introduced into organic chemistry. In particular, more and more catalytic applications are directed towards the use of chiral ligands, the synthesis of optically active compounds being a constant challenge for the pharmaceutical industry. In the latter area, the discovery of the nonlinear effect in asymmetric catalysis by Kagan represented a particularly important breakthrough. 

In 1966, Nozaki et al. reported that the decomposition of o-diazo-esters by a copper chiral Schiff base complex in the presence of olefins gave optically active cyclopropanes (Scheme 58).220 221 Following this seminal discovery, Aratani et al. commenced an extensive study of the chiral salicylaldimine ligand and developed highly enantioselective and industrially useful cyclopropanation.222-224 Since then, various complexes have been prepared and applied to asymmetric cyclo-propanation. In this section, however, only selected examples of cyclopropanations using diazo compounds are discussed. For a more detailed discussion of asymmetric cyclopropanation and related reactions, see reviews and books.17-21,225... 

Of great importance was the discovery by Johnson et al. (185) of the stereospecific synthesis of optically active sulfonimidoyl chlorides, which are key substrates for making new types of sulfonimidoyl compounds. The method involves chlorination of readily available chiral sulfinamides with chlorine or A/-chlorobenzotriazole. Scheme 12 summarizes the synthesis of (-)-(/ )-A/-methylphenylsulfonimidoyl chloride 163 from (+HS>N-methyl benzenesulfinamide 164 and its reactions with sodium phenoxide and dimethylamine. 

The importance of the theory was further demonstrated by the discovery of the existence of optically active inorganic compounds, and the isolation of the exact number of optical isomers theoretically possible for the spatial arrangement of the atoms.1 Friend 2 and others criticised the theory on the grounds that in simple compounds, such as sodium chloride or cobaltous chloride, the chlorine is ionised and yet is attached to sodium or cobalt atom directly, whereas in the ammino-coinpounds the acid capable of ionisation is that which is not directly attached to metal. For instance, in chloro-pentammino-cobaltic chloride, [CoCI(NH3)5]C12, it is the chlorine outside the first zone which is ionised in solution. Also, the dissociable acidic groups are not attached to any point within the complex, but simply hover round the central complex in an indefinite manner. Thus a definite valency for ionisable... 

New procedures for the synthesis of inorganic complexes have made it possible to prepare several new types of compound. Particularly noteworthy is the discovery by Shibata and his coworkers that the carbonato groups of [Co(C03)3]3 can be displaced stepwise, so that ligands of three different kinds can be introduced readily and compounds such as [Co(en)(pn)(N02)2]+ and [Co(NH3)2(H20)2(CN)2]+ can be prepared.6 The tris-carbonato complex can be obtained in optically active form. 

Synthetic pyrethroids are a group of ester compounds having excellent insecticidal activities. After the discovery of allethrin (1), a variety of useful synthetic pyrethroids have been produced mainly by structural modification of an alcohol having an asymmetric center. The insecticidal activities greatly depend upon the stereoisomers. Therefore, much effort has been expended to develop technologies for obtaining optically active isomers. However, contrary to the case of chrysanthemic acid, chemical methods of optical resolution were not very effective for these alcohols. 

Lets look at one more exampte of a compound with two chirality centers tartaric acid. We re already acquainted with tartaric acid because of its role in Pasteur s discovery of optical activity, and wv can now draw the four stereoisomers ... 

Until the discoveries of Werner, it was thought that the presence of carbon in a compound was required for it to be optically active. Werner prepared the following compound containing OH- ions as bridging groups and then separated the optical isomers. 

Cince Werner s early paper 19, 20) on the optical activity he postulated and discovered in coordination compounds, there have been several discoveries closely related to this work. One of these is the observation by Pfeiffer and Quehl 15) that the optical rotation of an aqueous solution containing an optically active substance (e.g., ammonium d-a-bromocamphor-TT-sulfonate, later referred to as the optically active en-vironment O be changed by adding solutions of racemic mixtures of certain coordination compounds (e.g., D,L-[Zn(o-phen)3](N03)2, where o-phen = or /io-phenanthroline). This effect has been referred to as the Tfeiffer effect in honor of its discoverer 3, 4) who first observed it during an attempted resolution of the racemic complex mentioned above 15). 

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