Chiral compounds asymmetry

Chiral separations are concerned with separating molecules that can exist as nonsupetimposable mirror images. Examples of these types of molecules, called enantiomers or optical isomers are illustrated in Figure 1. Although chirahty is often associated with compounds containing a tetrahedral carbon with four different substituents, other atoms, such as phosphoms or sulfur, may also be chiral. In addition, molecules containing a center of asymmetry, such as hexahehcene, tetrasubstituted adamantanes, and substituted aHenes or molecules with hindered rotation, such as some 2,2 disubstituted binaphthyls, may also be chiral. Compounds exhibiting a center of asymmetry are called atropisomers. An extensive review of stereochemistry may be found under Pharmaceuticals, Chiral. 

It is often possible to convert an achiral compound to a chiral compound by (1) addition of a chiral group (2) running an asymmetric synthesis, and (3) cleavage of the original chiral group. An example is conversion of the achiral 2-pentanone to the chiral 4-methyl-3-heptanone (50). In this case, >99% of the product was the (5) enantiomer. Compound 49 is called a chiral auxiliary because it is used to induce asymmetry and then is removed. 

In asymmetric synthesis, a chiral compound is synthesized from an achiral precursor in such a way that the formation of one enantiomer predominates over the other.23 The asymmetry of the reaction is induced by the presence of a diastereomeric complex and is a result of the formation of two distinct diastereomeric transition states separated in energy by the amount AAG >0. The ratio of the rate constants for the formation of the two enantiomers, kR and ks, is related to AAG according to equation (2.1.1 ).25 Assuming a kinetically controlled reaction, the kR/ks ratio will be reflected in the relative amount of each enantiomer formed. 

This chapter deals with one possible determinate mechanism, i.e., the role spin-polarized electrons might play in inducing an ee in chiral compounds. Of all the determinate mechanisms, probably the most discussed is the application of circularly polarized light (CPL) to induce asymmetry in a photolytic reaction. For a detailed discussion of this area the interested reader is recommended to several reviews in this area [13-17] and, in particular, the recent book by Meierhenrich [18]. For comparative purposes we will briefly go over the salient points of asymmetric chemistry induced by CPL. 

There are two ways of obtaining chiral substances using a chiral crystal environment. One is to produce the chiral compounds from the prochiral ones, and the other is to obtain the chiral compounds from racemic ones. The former method is called absolute asymmetric synthesis, since the asymmetry is introduced from the physical conditions such as the chiral crystal environment. Several examples [ 1 -7] have been reported since the first example of the chiral polymer produced in the photopolymerization of the chiral monomer crystal [8]. We also observed that chiral 3-lactam compounds were produced from the prochiral oxoamide crystals [9,10]. 

CCCs may be companies that specialize in chiral compounds, such as Celgene, Chiroscience, and Oxford Asymmetry, or may have developed into a chiral raw material supplier to an industry other than its original main customer base [e.g., Takasago, a flavor manufacturer, who developed a catalytic route to (-)-menthol, and used related technology to make beta-lactam intermediates]. 

Medium and minor players will typically have an exploitable intellectual property base from which they are developing or seeking to establish themselves chiral compounds are often the only products offered. However, as potential commercial suppliers at scale, they will be dependent on subcontracted production, including alliances with larger companies with available production capacity or significant capital investment. Examples are Synthon Corporation, which makes C4 synthons from carbohydrate raw materials, and Oxford Asymmetry, which exploits S. Davies work and patents and is in alliance with Cambrex. Customers will need to assess the adequacy of financial arrangements and/or the suitability of the chosen production partner. 

As mentioned in the introduction, chiral compounds can exhibit chiral mesophases and these are important due to the important physical properties that they may exhibit, including thermochroism, ferroelectric and electroclinic effects [15], In 1975, Meyer predicted the existence of a spontaneous polarization (Pg) in chiral, tilted smectic phases [86], and the existence of such polar order within a liquid crystal phase has important implications both scientifically and industrially [19]. The asymmetry associated with the chirality may also produce a beneficial lowering of transition temperatures. 

Chiral compounds can behave as catalysts in organic reactions. For example, chiral nitrogen bases, chiral crown ethers or Lewis adds bearing chiral residues catalyze diverse types of reactions. Asymmetry can also be induced in transition-metal-catalyzed reactions if the metal bears dural ligands. These possibilities will be described in sequence. 

The palladium-catalysed oxyamination of olefins is well known, and it has now been found that, by the use of chiral reagents, asymmetry can be induced in the amination step and that optically active tertiary amino-alcohols result. 1-Piperidino-l-trimethylsilyloxycyclopropane and the corresponding 1-hydroxy-compound have been prepared and examined for their utility as cyclopropanone equivalents. ... 

Also due to the high barrier of inversion, optically active oxaziridines are stable and were prepared repeatedly. To avoid additional centres of asymmetry in the molecule, symmetrical ketones were used as starting materials and converted to oxaziridines by optically active peroxyacids via their ketimines (69CC1086, 69JCS(C)2648). In optically active oxaziridines, made from benzophenone, cyclohexanone and adamantanone, the order of magnitude of the inversion barriers was determined by racemization experiments and was found to be identical with former results of NMR study. Inversion barriers of 128-132 kJ moF were found in the A-isopropyl compounds of the ketones mentioned inversion barriers of the A-t-butyl compounds lie markedly lower (104-110 kJ moF ). Thus, the A-t-butyloxaziridine derived from adamantanone loses half of its chirality within 2.3 days at 20 C (73JCS(P2)1575). 

Reductive alkylation with chiral substrates may afford new chiral centers. The reaction has been of interest for the preparation of optically active amino acids where the chirality of the amine function is induced in the prochiral carbonyl moiety 34,35). The degree of induced asymmetry is influenced by substrate, solvent, and temperature 26,27,28,29,48,51,65). Asymmetry also has been obtained by reduction of prochiral imines, using a chiral catalyst 44). Prediction of the major configurational isomer arising from a reductive alkylation can be made usually by the assumption that amine formation comes via an imine, not the hydroxyamino addition compound, and that the catalyst approaches the least hindered side (57). 

Epoxides bearing electron-withdrawing groups have been most commonly synthesized by the Darzens reaction. The Darzens reaction involves the initial addition of an ct-halo enolate 40 to the carbonyl compound 41, followed by ring-closure of the alkoxide 42 (Scheme 1.17). Several approaches for inducing asymmetry into this reaction - the use of chiral auxiliaries, reagents, or catalysts - have emerged. 

Palladium-catalysed asymmetrie allylations of various carbonyl compounds have been studied by Hiroi et al. using various types of chiral sulfonamides derived from a-amino acids. In particular, the chiral bidentate phosphinyl sulfonamide derived from (5)-proline and depicted in Scheme 1.63 was employed in the presence of palladium to eatalyse the allylation of methyl aminoacetate diphenyl ketimine with allyl aeetate, leading to the eorresponding (7 )-product with a moderate enantioseleetivity of 62% ee. This ligand was also applied to the allylation of a series of other nueleophiles, as shown in Seheme 1.63, providing the eorresponding allylated produets in moderate enantioseleetivities. 

One of the fundamental concepts of structural chemistry is that of molecular asymmetry or chirality. The most typical example is that of a tetrahedral carbon atom with four different substituents, C(abcd), which can produce two different arrangements, which are nonsuperimposable mirror images of one another. Such a carbon atom is usually called asymmetric or chiral. In contrast, when two of the substituents are alike, as in C(abc2), the system is usually termed symmetrical or achiral, except for a special class of compounds... 

W. Nerinckx, M. Vandewalle, Asymmetric Alkylation of a-Aryl Substituted Carbonyl Compounds by Means of Chiral Phase Transfer Catalysts. Applications for the Synthesis of (+)-Podocarp-8(14)-en-13-one and of (-)-Wy-16,225, A Potent Analgesic Agent , Tetrahedron Asymmetry 1990,1, 265-276. 

Lord Kelvin lla> recognized that the term asymmetry does not reflect the essential features, and he introduced the concept of chiralty. He defined a geometrical object as chiral, if it is not superimposable onto its mirror image by rigid motions (rotation and translation). Chirality requires the absence of symmetry elements of the second kind (a- and Sn-operations) lu>>. In the gaseous or liquid state an optically active compound has always chiral molecules, but the reverse is not necessarily true. 

During the coverage period of this chapter, reviews have appeared on the following topics reactions of electrophiles with polyfluorinated alkenes, the mechanisms of intramolecular hydroacylation and hydrosilylation, Prins reaction (reviewed and redefined), synthesis of esters of /3-amino acids by Michael addition of amines and metal amides to esters of a,/3-unsaturated carboxylic acids," the 1,4-addition of benzotriazole-stabilized carbanions to Michael acceptors, control of asymmetry in Michael additions via the use of nucleophiles bearing chiral centres, a-unsaturated systems with the chirality at the y-position, and the presence of chiral ligands or other chiral mediators, syntheses of carbo- and hetero-cyclic compounds via Michael addition of enolates and activated phenols, respectively, to o ,jS-unsaturated nitriles, and transition metal catalysis of the Michael addition of 1,3-dicarbonyl compounds. ... 

Molecular asymmetry, chirality and enantiomers The observation of Louis Pasteur (1848) that crystals of certain compounds exist in the form of mirror Images laid the foundation of modem stereochemistry. He demonstrated that aqueous solutions of both types of crystals showed optical rotation, equal in magnitude (for solution of equal concentration) but opposite in direction. He believed that this difference in... 

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