Small-molecule compounds enantiomers

Pharmaceutical companies have switched to single enantiomer (enantiopure) chiral chugs. This trend is indicated by the fact that in 2006, 80% of the small molecule chugs approved by FDA were chiral and 75% were single enantiomers. It is expected that 200 chiral compounds could enter the development process every year... 

The development of enantioselective chemical processes is critical to the preparation of enantiomerically pure bioactive compounds. Roughly 75% of small molecule pharmaceuticals are marketed in enantiomerically pure form [1], Enantioselective chemical processes require the use of chiral media that drive chemical reactions kinetically to produce one of two enantiomers selectively. Many such enantioselective... 

There are many directions in which this can proceed. This review, however, will be for reasons of subject matter and space restricted to a state-of-the-art discussion of only one aspect of such work. This aspect will be the bioorganic modelling of certain enzymic processes with fairly small molecules, naturally occurring or synthetic, which have the ability to complex the substrate in a rapid pre-equilibrium, just as in an enzyme. Because of the subject content of this book these compounds will be in almost all cases macrocycles and they will usually have also the capacity for the recognition of enantiomers of a potential substrate. 

In 1971, Davankov et al. achieved the first baseline separation of enantiomers using a small molecule-based CSP consisting of L-proline [1], Since then, a wide range of chiral small compounds, which include amino acids, cyclodextrins, macrocyclic glycopeptides, cinchona alkaloids, crown ethers, jt-basic or rt-acidic aromatic compounds, etc., have been used as CSPs [2—6], On the other hand, the polymer-based CSPs are further divided into two categories, i.e., synthetic and natural chiral polymers [7, 8]. Typical examples of the synthetic polymers are molecularly imprinted polymer gels, poly(meth)acrylamides, polymethacrylates, polymaleimides, and polyamides, and those of the natural polymers include polysaccharide derivatives and proteins. 

There are many classes of CSPs applicable in different mobile-phase modes. In particular, CSPs based on derivatized polysaccharides, native and derivatized cyclodextrins, macrocyclic glycopeptides, and Pirkle-type chiral selectors operate quite well in four separation modes, i.e RP, polar organic phase, NP, and super- or subcritical fluid chromatography (SFC) conditions. It is common that a chiral compound can be separated on the same CSP in more than one separation mode [58, 160, 166, 170-176]. For example, Nutlin-3, a small molecule antagonist of MDM2, has been baseline resolved from its enantiomer in all four mobile-phase conditions (Fig. 16) [170]. Multimodal enantioseparation on the same CSP would be greatly beneflcial for chiral method development in pharmaceutical industry. 

Enantiomericaiiy pure amines are commonly used as precursors for active pharmaceutical ingredients (APIs). In 2013, one in four of the top 200 selling drugs contained a chiral amine moiety [9]. In addition, chemical synthesis of these enantiomericaiiy pure amines is critical as 80% of small-molecule pharmaceutical dmgs approved by the FDA in 2006 contained chiral centers and 75% were single enantiomers [10]. Chiral amine compounds with high optical purities can be difficult to prepare by many types of traditional catalysts. 

This technique is a variant of CZE. A cationic or anionic surfactant compound, such as sodium dodecylsulphate, is added to the mobile phase to form charged micelles. These small spherical species, whose core is essentially immiscible with the solution, trap neutral compounds efficiently by hydrophylic/hydrophobic affinity interactions (Fig. 8.7). Using this type of electrophoresis, optical purity analysis can be conducted by adding cyclodextrins instead of micelles to the electrolyte. This is useful for separating molecules that are not otherwise separable. Under such conditions, the enantiomers form inclusion complexes of different stability with cyclodextrin (cf. 3.6). 

The enantiomers shown are related as a right-hand and left-hand screw, respectively. Chiral allenes are examples of a small group of molecules that are chiral, but don t have a chirality center. What they do have is a chirality axis, which in the case of 2,3-pentadiene is a line passing through the three carbons of the allene unit (carbons 2, 3, and 4). The Cahn-Ingold-Prelog R-S notation has been extended to chiral allenes and other molecules that have a chirality axis. Such compounds are so infrequently encountered, however, we will not cover the rules for specifying their stereochemistry in this text. 

The formation of two-dimensional nanocrystals, by peptide amphiphiles is also influenced by the chirality of the peptide building block.125 Three types of two-dimensional crystals were observed after the assembly of the functionalized peptide amphiphiles 17-19 shown in Figure 7.11 (above) at the air-water interface, which was followed by polymerization. These two dimensional crystals include (/) a racemic compound, in which each enantiomer is packed with its mirror image in a crystalline order, (it) enantiomorphous conglomerates, in which each enantiomer is segregated into small domains, and (iii) a solid solution, in which all molecules are randomly distributed without crystalline order. Interestingly, in the case of the two-dimensional system arising from the racemic compound,... 

The term racemate refers to any mixture of equal or nearly equal amounts of enantiomeric molecules. In reference to solid state properties, the most common type of racemate is a racemic compound, in which each crystal, no matter how small, is racemic. The racemic conglomerate or mixture, such as Fhsteur resolved, is much less commonly encountered. In this case, each crystal is composed entirely of the same enantiomer, but the bulk sample approaches a 1 1 ratio. 

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