Stereoselective reactions, 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. 

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. 

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. 

Our objective in this paper is to present precise descriptions for these concepts and thereby attain an objective general definition of asymmetric synthesis . We illustrate use of this definition in a broad variety of stereoselective reactions those reactions generally counted to be asymmetric do in fact turn out to be asymmetric by our criterion, and some of those whose asymmetry is controversial do not constitute asymmetric syntheses by our definition. 

The condition 1) states that unequal amounts of stereoisomers are produced or destroyed by the reaction together conditions 2) and 3) assure that the increase in chiral genus is due to a stereoselectivity which is caused by chiral influences alone. Condition 1) is an essential part of the definition it is interrelated with condition 3), and together they restrict the type of chirality increasing stereoselective reactions that will be called an asymmetric synthesis34. In fact, a stereoselective reaction is never infinitely selective , because this would require an infinite free enthalpy difference of stereoisomers, stereoisomeric transition states respectively (with thermodynamic control, or with productive selectivity) in the case of an idealized destructive selectivity infinite selectivity would be reached at infinite reaction time, when none of the considered stereoisomers would be left over3S ... 

It will be appreciated that, with these definitions, any stereospecific process is also stereoselective however, not all stereoselective reactions are stereospecific. In some papers, the terms are modified with the prefixes, enantio- or diastereo-. 

For the purposes of this treatise, the definition of asymmetric synthesis is a modification of that proposed by Morrison and Mosher [1] and as such will be applied to stereospecific reactions in which a prochiral unit in either an achiral or a chiral molecule is converted, by utility of other reagents and/or a catalytic antibody, into a chiral unit in such a manner that the stereoisomeric products are produced in an unequal manner. As such, the considerable body of work devoted to antibody-catalysis of stereoselective reactions including chiral resolutions, isomerizations and rearrangements are considered to be beyond the scope of this discussion. For information regarding these specific topics and more general information regarding the catalytic antibody field the following papers... 

Following our definition of stereospecificity given above, it follows that both stereoselective reactions (transformations (155-163a/b) and nonstereoselective ones (transformations 157a/b-163a/b) can be stereospecific. Therefore, the first part of the statement "all stereospecific processes are stereoselective, but all stereoselective processes are stereospecific " is not true. By our definition, all stereospecific processes are not stereoselective for example, stereospecific transformations 157a/b-163a/b can be nonstereoselective. 

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. 

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-... 

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. 

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. 

Let us now define three terms that refer to reactions stereoselective, stereospecific and stereoelectronic. There has been a difference of opinion about the use of the first two we shall use the definitions suggested by Zimmerman2 and now adopted by most authors. 

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