Stereogenic unit

The stereochemical analysis of chiral structures starts with the identification of stereogenic units [101], Those units consist of an atom or a skeleton with distinct ligands. By permutation of the ligands, stcrcoisomcric structures arc obtained. The three basic stereogenic units arc a center of chirality (c.g., a chiral tctravalcnt... 

Figure 2-70. Examples of chiral molecules with different types of stereogenic units.

In chemoinformatics, chirality is taken into account by many structural representation schemes, in order that a specific enantiomer can be imambiguously specified. A challenging task is the automatic detection of chirality in a molecular structure, which was solved for the case of chiral atoms, but not for chirality arising from other stereogenic units. Beyond labeling, quantitative descriptors of molecular chirahty are required for the prediction of chiral properties such as biological activity or enantioselectivity in chemical reactions) from the molecular structure. These descriptors, and how chemoinformatics can be used to automatically detect, specify, and represent molecular chirality, are described in more detail in Chapter 8. 

If, on the other hand, the aldol addition is performed using either enolates with stereogenic units, which may be located in the a-substituent Y or in the ipso-substituent X, or using chiral aldehydes, the aldol products 4a, 5a and 6a arc diastcreomers with respect to 4b, 5b and 6b. Thus, both significant simple diastereoselectivity and induced stereoselectivity are highly desirable when ... 

In principle, asymmetric synthesis involves the formation of a new stereogenic unit in the substrate under the influence of a chiral group ultimately derived from a naturally occurring chiral compound. These methods can be divided into four major classes, depending on how this influence is exerted (1) substrate-controlled methods (2) auxiliary-controlled methods (3) reagent-controlled methods, and (4) catalyst-controlled methods. 

The substrate-controlled reaction is often called the first generation of asymmetric synthesis (Fig. 1-30, 1). It is based on intramolecular contact with a stereogenic unit that already exists in the chiral substrate. Formation of the new stereogenic unit most often occurs by reaction of the substrate with an achiral reagent at a diastereotopic site controlled by a nearby stereogenic unit. 

In all three of the above-mentioned chiral transformations, stoichiometric amounts of enantiomerically pure compounds are required. An important development in recent years has been the introduction of more sophisticated methods that combine the elements of the first-, second-, and third-generation methods and involve the reaction of a chiral substrate with a chiral reagent. The method is particularly valuable in reactions in which two new stereogenic units are formed stereoselectively in one step (Fig. 1-30, 4). 

In fact, compounds 31 and 32 from Ancistrocladus hamatus have the same configuration in the axial stereogenic unit (atriousiners) but opposite configuration for the two stereogenic centers of the tetrahydroisoquinoline ring. 

The essence of asymmetric synthesis is producing a new stereogenic center in such a manner that the product consists of stereoisomers in unequal amount. In most cases, this can be achieved by the formation of a new sp3 stereocenter. There is also another type of asymmetric reaction in which the employed substrates contain either a stereogenic unit or a pro-stereogenic unit apart from the functional group, and asymmetric synthesis occurs even though the nature of the reaction is not directly related to the newly formed sp3 stereocenter. The Wittig reaction is invoked for the asymmetric synthesis of such molecules.47... 

Different types of the reagents (see Fig. 8-4) have been applied in asymmetric Wittig-type reactions. Because no new sp3 stereocenter is formed in a Witting-type reaction, a substrate containing a stereogenic or pro-stereogenic unit apart from the carbonyl group is usually required to induce an asymmetric process. 

The intramolecular cycloaddition of nitrile oxides to substituted furans was reported to occur with low stereoselectivity (274). Inserting a stereogenic unit within the chain connecting the dipole and dipolarophile did not increase the stereoselectivity (274). 

Examples of models with two stereogenic units, two-dimensional enantiomers, and familiar examples of diastereomers are illustrated by examples 5-7. 

For olefins, the Ikjul specification obviously constitutes an alternative to the familiar ZjE description. However, there is no direct equivalence (see examples 5a and 6) because these specifications are based on different stereogenic units. The Ikjul description involves the inner trigonal centers of the double bond which is not the case for ZfE descriptors which are based on a rectangular arrangement of the ligands only. 

The description of stereoisomers is related to analysis in terms of the four-point figures discussed in the previous section. However, these units are seldom encountered unobscured. More common are certain partially overlapping combinations (see Table 1), stereogenic units, analysis of which is an important problem. A stereogenic unit consists of a core of bonds and ligands. 

In analogy to the case of the two-dimensional pseudoasymmetric center (see Section 1.1.2.2.) pseudoasymmetric stereogenic units are encountered when enantiomorphic ligands (F/F) are located in positions of the core (with residual ligands), that are reflection equivalent but not rotationally equivalent, i.e., in enantiotopic positions. Again, lowercase letter descriptors (r/s, pjm) are used in order to express invariance to reflection. The previous criticism concerning the term pseudoasymmetric (see Section 1.1.2.2.) also applies here and will be elaborated in Section 1.1.3.5. 

Fortunately, the original assignment rule for the chirality plane is identical to the helieity assignment defined above with descriptors aRjaS and PjM, respectively, corresponding. However, the rule for the chirality axis was based on an elongated tetrahedron as the stereogenic unit and the descriptors aR and P or aS and M are not equivalent ... 

When the four ligands have been ordered, the stereogenic units are assigned descriptors in the usual manner (see Section 1.1.3.). The term assignment rule appears to be more appropriate than the previously used conversion2 or chirality rule3. 

Finally, it could be asked why it is so important to properly identify stereogenic centers and prefer them to helical units The main practical reason is that most molecules, when realistically described, e.g., by a crystal structure, contain numerous helical units and it is exceedingly difficult, particularly with a computer program, to sort out those that are invariant to physical conditions (see Section 1.1.1.). In general, it is advisable to base specification of stereogenic units on constitutional or configurational distinctions of ligands, as these are normally less affected by external conditions than conformational properties. 

Mislow and Siegel11 criticized the CIP system, inter alia, by totally denying symmetry-adaptation of it. The above enumeration, however, should suffice to demonstrate that this disqualification is certainly not appropriate for stereogenic units of tpye 1. Their comments on "pseudoasymmetric centers 11 unfortunately use varying viewpoints and make erroneous assignments of descriptors. The point at issue, which is of fundamental significance, is best explained by the examples 1, 2, and ent-2, also used by these authors. 

The description of stereoselective reactions in which one new stereogenic unit is created, i.e., where a pair of enantio- or diastereomers can result, is straightforward. However, there are now numerous examples known of stereoselective reactions in which two or more stereogenic units are generated in the bond-forming step. Accordingly, more than two stereoisomers are formed. In principle, stating the ratio of the stereoisomeric products would suffice for the description of the outcome of such a reaction. However, mechanistic rationalization and prediction of the results are vastly simplified when subsets of the stereoisomers and their relative ratios are considered. Here the terms simple and induced diastereoselectivity play an important practical role. 

Most, but not all, pertinent examples concern the formation of stereogenic units by additions to olefins or face-to-face combinations of trigonal planar units, c.g., aldol-type additions, as illustrated in Table 15. 

Simple diastereoselectivity ratio of diastereomers with different relative configurations of the new stereogenic units. 

Auxiliary-Induced Stereoselectivity Stereoselectivity in a sequence of reactions leading to a synthetic target is auxiliary induced when (a) new stereogenic unit(s) is (are) diastereose-lectively generated in a molecule containing a covalently bound chiral unit that is removed after the diastereoselective step. 

Izumi and Tai29 discussed Horeau s results but used, for the same issue, the term double-differentiating reaction . With respect to terminology, there is an important difference between stereoselectivity and stereodifferentiation that will be outlined in the following section. Accordingly, there is a necessity for a definition double asymmetric induction is applied when a stereogenic unit(s) is (are) generated from two reactants that are both chiral or from one chiral reactant in the presence of a chiral additive. 

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