Stereoselectivity, definition

The form of the Hammond postulate just presented is very important in the analysis of the selectivity of many of the reactions we will discuss in this book in connection with chemoselectivity (definition in Section 1.7.2 also see Section 3.2.2), stereoselectivity (definition in Section 3.2.2), diastereoselectivity (definition in Section 3.2.2), enantiose-lectivity (definition in Section 3.2.2), and regioselectivity (definition in Section 1.7.2). 

However, if both maleic and fumaric acid gave the dl pair or a mixture in which the dl pair predominated, the reaction would be stereoselective but not stereospecific. If more or less equal amounts of dl and meso forms were produced in each case, the reaction would be nonstereoselective. A consequence of these definitions is that if a reaction is carried out on a compound that has no stereoisomers, it cannot be stereospecific, but at most stereoselective. For example, addition of bromine to methylacetylene could (and does) result in preferential formation of trans-1,2-dibromopropene, but this can be only a stereoselective, not a stereospecific reaction. 

Of course, the trans isomer will give the opposite results the threo pair if the addition is syn and the erythro pair if it is anti. The threo and erythro isomers have different physical properties. In the special case where Y=W (as in the addition of Br2), the erythro pair is a meso compound. In addition to triple-bond compounds of the type ACsCA, syn addition results in a cis alkene and anti addition in a trans alkene. By the definition given on page 166 addition to triple bonds cannot be stereospecific, though it can be, and often is, stereoselective. 

To date, direct asymmetric synthesis of optically active chiral-at-metal complexes, which by definition leads to a mixture of enantiomers in unequal amounts thanks to an external chiral auxiUary, has never been achieved. The most studied strategy is currently indirect asymmetric synthesis, which involves (i) the stereoselective formation of the chiral-at-metal complex thanks to a chiral inductor located either on the ligand or on the counterion and then (ii) removal of this internal chiral auxiliary (Fig. 4). Indeed, when the isomerization of the stereogenic metal center is possible in solution, in-... 

This quantity represents the energy of the multiple-site charge-transfer interaction which will later play an important role in the theory of stereoselection. It is to be remarked that, although any MO may involve an arbitrary constant of which the absolute value is unity, the value of the numerator in each term of the right side of this equation is always definite. 

Recently, Denmark and coworkers have developed a new strategy for the construction of complex molecules using tandem [4+2]/[3+2]cycloaddition of nitroalkenes.149 In the review by Denmark, the definition of tandem reaction is described and tandem cascade cycloadditions, tandem consecutive cycloadditions, and tandem sequential cycloadditions are also defined. The use of nitroalkenes as heterodienes leads to the development of a general, high-yielding, and stereoselective method for the synthesis of cyclic nitronates (see Section 5.2). These dipoles undergo 1,3-dipolar cycloadditions. However, synthetic applications of this process are rare in contrast to the functionally equivalent cycloadditions of nitrile oxides. This is due to the lack of general methods for the preparation of nitronates and their instability. Thus, as illustrated in Scheme 8.29, the potential for a tandem process is formulated in the combination of [4+2] cycloaddition of a donor dienophile with [3+2]cycload-... 

A definitive feature of this highly stereoselective new route to substituted tetrahydrofurans is that both syn and anti allylic diol stereoisomers typically afford identical tetrahydrofuran products. Thus, there is no need for stereoselective... 

The most famous mechanism, namely Cossets mechanism, in which the alkene inserts itself directly into the metal-carbon bond (Eq. 5), has been proposed, based on the kinetic study [134-136], This mechanism involves the intermediacy of ethylene coordinated to a metal-alkyl center and the following insertion of ethylene into the metal-carbon bond via a four-centered transition state. The olefin coordination to such a catalytically active metal center in this intermediate must be weak so that the olefin can readily insert itself into the M-C bond without forming any meta-stable intermediate. Similar alkyl-olefin complexes such as Cp2NbR( /2-ethylene) have been easily isolated and found not to be the active catalyst precursor of polymerization [31-33, 137]. In support of this, theoretical calculations recently showed the presence of a weakly ethylene-coordinated intermediate (vide infra) [12,13]. The stereochemistry of ethylene insertion was definitely shown to be cis by the evidence that the polymerization of cis- and trans-dideutero-ethylene afforded stereoselectively deuterated polyethylenes [138]. 

An interesting pericyclic-anionic-pericyclic domino reaction showing a high stereoselectivity is the cycloaddition-aldol-retro-ene process depicted in scheme 20.1581 The procedure presumably starts with a [4+2]-cycloaddition of diene 98 and S02 in presence of a Lewis acid. After opening of the formed adduct reaction with (Z)-silyl vinyl ether 99 leads to a mixture of alk-2-enesulfinic acids 101. It follows a retro-ene reaction which affords a 7 3 mixture of the products 102 and 103. The reaction described by Vogel et al is a nice example for the efficient generation of polypropionate chains with the stereoselective formation of three stereogenic centers and one (0-double bond in a three-component domino reaction in its strict definition. 

On the other hand, selective, usually applied to a synthesis, means that of all the possible isomers only one isomer is obtained. However, if the reaction product was/is a mixture of isomers one could speak then of the "degree of selectivity". Since usually one of the isomers will be the predominant isomer, we may say that the reaction (or the synthesis) is selective with respect to this particular isomer. As in the case of "specificity", we may refer to "regioselectivity" or to "stereoselectivity" (either diastereoselectivity or enantioselectivity) and may say, for instance, that a synthesis is 80% diastereoselective. According to the most updated terminology "diastereomers" are all the "stereoisomers" that are not "enantiomers", so geometrical isomers are also included in such a definition. 

A stereospecific chemical reaction is one in which starting substrates or reactants, differing only in their configuration, are converted into stereoisomeric products. Note, with this definition a stereospecific reaction has to be stereoselective whereas the inverse statement (that is, with respect to a stereoselective reaction or process) is not necessarily true. 2. Referring to reactions that act on only one stereoisomer (or, have a preference for one stereoisomer). Thus, many enzyme-catalyzed reactions are stereospecific, and characterization of that stereospecificity is always an issue to be addressed for a particular enzyme. 

In addition to identification of flavan-3-ols and derivatives from natural sources (Table 11.3, Figure 11.3-Figure 11.5, Figure 11.7, and Figure 11.8), several synthetic studies and efforts at establishing absolute configuration have been reported. The modified Mosher method has been successfully applied to configurational definition of the flavan-3-ols and 4-arylflavan-3-ols, and the A-type proanthocyanidins. " The first stereoselective synthesis of a series of flavan-3-ol... 

Lehman et al. (1986) stated the definitions of stereoselectivity in the following manner the better fitting enantiomer (the one with higher affinity for the receptor) is called the eutomer, whereas the one with the lower affinity is called the distomer. The ratio of... 

In a series of agonists and antagonists (for definitions, see section 2.4), the eudismic affinity quotient can also he defined as a measure of stereoselectivity. Because of widespread misconceptions, the distomer of a racemate is often considered inactive and of no consequence to pharmacological activity, an idea reinforced by the fact that resolution (i.e., separation) of racemates is economically disadvantageous. In the 1980s, Ariens and his associates (Ariens et al., 1983 Ariens, 1984, 1986) published a series of influential books and papers that showed the fallacy of this concept and pointed out the necessity of using pure enantiomers in therapy and research thankfully, this message has now been learned. 

It is the purpose of this section to provide the modern vocabulary required for the description of stereoselective reactions. This also implies the description of stereochemical aspects of starting materials and products, i.e., aspects of static stereochemistry. The material has been arranged in logical progression and, whenever possible, rules and directions for use or explicit definitions of important terms are given. 

In retrospect, it seems unfortunate that in 1971 Morrison and Mosher8 generalized the definition, while keeping the term, an asymmetric synthesis is a reaction in which an achiral unit in an ensemble of substrate molecules is converted by a reactant into a chiral unit in such a manner that the stereoisomeric products arc produced in unequal amounts ( Footnote The substrate molecule must have either enantiotopic or diastereotopic groups or faces) . Obviously the phrase "an achiral unit in an ensemble of substrate molecules is too inexact and requires a great deal of additional explanation, which was partially given by the footnote (note that molecule, i.e., singular, was used ). Currently, the Morrison-Mosher term appears to be equivalent to stereoselective reaction. Unfortunately, this term was only defined in the modem sense by Izumi in 1971, i.e., in the same year the Morrison-Mosher definition was published. 

This classification, defined in Table 13 with examples, appears very clear and logical in view of the standard classification of isomers. However, the historical development followed a rather curious course. The term constitutional selectivity, unfortunately a somewhat clumsy word which is rarely used, appeared in the literature as late as 1979 -2. This was after an inspiring, but not completely clear, discourse by Hassner on the almost equivalent term regioselectivity which greatly appealed to chemists and was immediately accepted. It is important to note that the now universally accepted definition of stereoselectivity and its subclasses enantio- and diastercoselectivity did not appear in print until as late as 19714. Before that, the term stereoselectivity apparently had the special meaning of the present term diastereoselectivity5. One consequence of this was discussed in the previous section. Furthermore, in the past, the terms selectivity and specificity were usually coupled. The latter term will be discussed in Section 1.2.3.3, but it is currently regarded with suspicion and best avoided. 

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. 

Furthermore, a clear definition of the term meso-trick is apparently not available. Seebach13 implies that the meso-trick involves an KPC synthesis which starts with a we.vocompound that is completely transformed, via a sequence of reactions involving a stereoselective reaction or resolution, into one enantiomer. 

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