Examples of Stereoselective Reactions

Unfunctionalized alkene usually reacts by preferential syn delivery of hydrogen from the less hindered face of the double bond. The degree of stereoselectivity is dependent on the reactant structure, catalysts and reaction conditions. Donor functional groups, particularly hydroxy and amino can be syn directive. 

Adjacent stereocenters influence the mode of addition of nucleophiles such as hydrides and organometallic reagents to acyclic ketones. The Felkin-Ahn transition state provides a predictive model that is general when steric effects are dominant. Other factors must be considered when polar or chelating substituents are present. 

In most cases, both hydrogen atoms are added to the same side of the reactant (syn addition). If hydrogenation occurs by addition of hydrogen in two steps, as implied by the mechanism above, the intermediate must remain bonded to the metal surface in such a way that the stereochemical relationship is maintained. Adsorption to the catalyst surface normally involves the less sterically congested face of the double bond, and as a result, hydrogen is added from the less hindered face of the molecule. There are many cases of hydrogenations where hydrogen addition is not entirely syn and independent corroboration of the stereochemistry is normally necessary. 

The facial stereoselectivity of hydrogenation is affected by the presence of polar functional groups that can influence the mode of adsorption to the catalyst surface. For 

Substiment directive effects are also observed with soluble (homogeneous) hydrogenation catalysts. A number of transition metal complexes function as homogeneous hydrogenation catalysts. Three important examples are shown below. 

---

Some stereospecific reactions are listed in Scheme 2.9. Examples of stereoselective reactions are presented in Scheme 2.10. As can be seen in Scheme 2.9, the starting materials in these stereospecific processes are stereoisomeric pairs, and the products are stereoisomeric with respect to each other. Each reaction proceeds to give a single stereoisomer without contamination by the alternative stereoisomer. The stereochemical relationships between reactants and products are determined by the reaction mechanism. Detailed discussion of the mechanisms of these reactions will be deferred until later chapters, but some comments can be made here to illustrate the concept of stereospecificity. 

Some examples of stereoselective reactions, involving bond formation at the least hindered side, opposite to an alkyl substituent, are shown below. 

It is an example of stereoselective reaction as it leads predominantly one form. 

Some stereospecific reactions are listed in Scheme 2.4. Examples of stereoselective reactions are presented in Scheme 2.5. As can be seen in Scheme 2.4, the starting materials in these stereospecific processes are stereoisomeric pairs and the products... 

Cycloaddition involves the combination of two molecules in such a way that a new ring is formed. The principles of conservation of orbital symmetry also apply to concerted cycloaddition reactions and to the reverse, concerted fragmentation of one molecule into two or more smaller components (cycloreversion). The most important cycloaddition reaction from the point of view of synthesis is the Diels-Alder reaction. This reaction has been the object of extensive theoretical and mechanistic study, as well as synthetic application. The Diels-Alder reaction is the addition of an alkene to a diene to form a cyclohexene. It is called a [47t + 27c]-cycloaddition reaction because four tc electrons from the diene and the two n electrons from the alkene (which is called the dienophile) are directly involved in the bonding change. For most systems, the reactivity pattern, regioselectivity, and stereoselectivity are consistent with describing the reaction as a concerted process. In particular, the reaction is a stereospecific syn (suprafacial) addition with respect to both the alkene and the diene. This stereospecificity has been demonstrated with many substituted dienes and alkenes and also holds for the simplest possible example of the reaction, that of ethylene with butadiene ... 

Thus, this first example of stereoselective radical reaction, initiated with the system based on Fe(CO)5, shows opportunities and prospects of using the metal complex initiators for obtaining the stereomerically pure adducts of bromine-containing compounds to vinyl monomers with chiral substituents. 

Some examples of alkylation reactions involving relatively acidic carbon acids are shown in Scheme 1.3. Entries 1 to 4 are typical examples using sodium ethoxide as the base. Entry 5 is similar, but employs sodium hydride as the base. The synthesis of diethyl cyclobutanedicarboxylate in Entry 6 illustrates ring formation by intramolecular alkylation reactions. Additional examples of intramolecular alkylation are considered in Section 1.2.5. Note also the stereoselectivity in Entry 7, where the existing branched substituent leads to a trans orientation of the methyl group. 

An extension of this method can be used to prepare allylic alcohols. Instead of being protonated, the (3-oxido ylide is allowed to react with formaldehyde. The (J-oxido ylide and formaldehyde react to give, on warming, an allylic alcohol. Entry 12 is an example of this reaction. The reaction is valuable for the stereoselective synthesis of Z-allylic alcohols from aldehydes.245... 

The focus of Part B is on the closely interrelated topics of reactions and synthesis. In each of the first twelve chapters, we consider a group of related reactions that have been chosen for discussion primarily on the basis of their usefulness in synthesis. For each reaction we present an outline of the mechanism, its regio- and stereochemical characteristics, and information on typical reaction conditions. For the more commonly used reactions, the schemes contain several examples, which may include examples of the reaction in relatively simple molecules and in more complex structures. The goal of these chapters is to develop a fundamental base of knowledge about organic reactions in the context of synthesis. We want to be able to answer questions such as What transformation does a reaction achieve What is the mechanism of the reaction What reagents and reaction conditions are typically used What substances can catalyze the reaction How sensitive is the reaction to other functional groups and the steric environment What factors control the stereoselectivity of the reaction Under what conditions is the reaction enantioselective ... 

This means that if a reaction is carried out on a compound that has no stereoisomers, it cannot be stereospecific but at most stereoselective. The concerted reactions, including SN2 displacements, E2 elimination of alkyl halides, anti and Syn addition to alkenes are all stereoselective. In the case of chiral or geometric substrates the nature of the product depends on the unique stereoelectronic requirement of the reaction. These are examples of stereospecific reactions. 

Another example of stereoselective radical cation addition was presented by Hirano and co-workers. The reaction of 1,1-diphenyl-l,n-alkadienes employing 1,4-dicyanobenzene as a sensitizer yielded intramolecular tandem cyclization products in up to 60% yield (Scheme 29) [40]. 

The use of chiral azomethine imines in asymmetric 1,3-dipolar cycloadditions with alkenes is limited. In the first example of this reaction, chiral azomethine imines were applied for the stereoselective synthesis of C-nucleosides (100-102). Recent work by Hus son and co-workers (103) showed the application of the chiral template 66 for the formation of a new enantiopure azomethine imine (Scheme 12.23). This template is very similar to the azomethine ylide precursor 52 described in Scheme 12.19. In the presence of benzaldehyde at elevated temperature, the azomethine imine 67 is formed. 1,3-Dipole 67 was subjected to reactions with a series of electron-deficient alkenes and alkynes and the reactions proceeded in several cases with very high selectivities. Most interestingly, it was also demonstrated that the azomethine imine underwent reaction with the electronically neutral 1-octene as shown in Scheme 12.23. Although a long reaction time was required, compound 68 was obtained as the only detectable regio- and diastereomer in 50% yield. This pioneering work demonstrates that there are several opportunities for the development of new highly selective reactions of azomethine imines (103). 

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. 

Until recently only a few examples of stereoselective alkylation reactions of localized carban-ions which proceed under auxiliary control have been reported. The reason is obviously to be found in the difficulty of generating such carbanions having no additional stabilization and, if generated, in the low nucleophilicity of these strongly basic reagents. 

Some further examples of stereoselective deprotonation/alkylation reactions of tricarbonyl-chromium complexed (V-methyl tetrahydroisoquinolines have been reported27. Starting with the enantiomerically pure (35)-methyl tetrahydroisoquinoline reaction with hexacarbonyl-chromium led to a mixture of endo- (40%) and exo- (60%) complexes, which were deprotonated with butyllithium and subsequently methylated with iodomethane. In this way methylation occurred firstly at the 4- and secondly at the 1-position. In all cases, the methyl group entered anti to the chromium complexed face. After separation of the alkylated complexes by chromatography and oxidative decomplexation, the enantiomerically pure diastereomers (—)-(l 5,35,47 )-and ( + )-(17 ,35,45)-1,2,3,4-tetrahydro-l,2,3,4-tetramethylisoquinolme were obtained, benzylic amines such as tetrahydroisoquinoline to 2-amino-4,5-dihydrooxazoles. Deprotona... 

Few examples of stereoselectivity in 6-exo cyclizations to piperidine derivatives have been reported. The aminocarbonylation reactions of systems with an allylic hydroxy substituent that are quite stereoselective in cyclization to pyrrolidine systems (equation 106) are nonselective in cyclizations to piperidine systems.237 Cyclizations with mercury(II) acetate also proceed with low selectivity (59-69% cis isomer).237 A series of aminoalditols have been synthesized by aminomercuration of oxygen-substituted 6-(/V-benzylamino)hexenes. The stereochemistry of these cyclizations (equation 112)247 does not appear... 

Recently the unprecedented example of stereoselective C—Si bond activation in cu-silyl-substituted alkane nitriles by bare CQ+ cations has been reported by Hornung and coworkers72b. Very little is known of the gas-phase reactions of anionic metal complexes with silanes. In fact there seems to be only one such study which has been carried out by McDonald and coworkers73. In this work the reaction of the metal-carbonyl anions Fe(CO) (n = 2, 3) and Mn(CO) (n = 3, 4) with trimethylsilane and SiH have been examined. The reactions of Fe(CO)3 and Mn(CO)4 anions exclusively formed the corresponding adduct ions via an oxidative insertion into the Si—H bonds of the silanes. The 13- and 14-electron ions Fc(CO)2 and Mn(CO)3 were observed to form dehydrogenation products (CO) M(jj2 — CH2 = SiMe2) besides simple adduct formation with trimethylsilane. The reaction of these metal carbonyl anions with SiFLj afforded the dehydrogenation products (CO)2Fe(H)(SiII) and (CO)3Mn(II)(SiII). ... 

A recent example of this reaction is the photo-irradiation of mixtures of benzaldehyde and substituted enamines to give 3-amino oxetanes with very high diastereoselectivities in favor of the fir-product <1999JOC1265>. High regio- and stereoselectivity were again achieved in reactions between monosubstituted benzils and 2-morpholinopropenenitrile... 

It has been long established that Lewis acid-catalysed [2+2] cycloaddition of ketenes and carbonyl compounds provides access to 2-oxetanones. In the development of this reaction prior to 1996, there has been a specific focus on controlling the stereochemistry of the /3-lactone product and cycloadditions have been achieved between trimethyl-silylketene and aldehydes with up to 90% stereoselectivity, as discussed in CHEC-II(1996) <1996CHEC-II(1)721>. CHEC(1984) and CHEC-II(1996) also discuss examples of the Lewis acid-catalyzed, nonphotolytic [2+2] cycloaddition of electron-rich alkenes with aldehydes or ketones <1984CHEC(7)363, 1996GHEC-II(1)721>. While this method can have some advantages over the photolytic reaction in terms of regioselectivity, no examples of this reaction have been reported in recent years. 

Particularly challenging is the use of chiral ligands in order to impose enan-tiocontrol on a Reformatsky reaction. Although preparatively useful levels of asymmetric induction have been described in the recent literature by using enantiomerically pure amino alcohol ligands43 this reaction has not yet reached a similar level of perfection as the enantioselective addition of other organozinc reagents to aldehydes in the presence of the same type of additives. Some selected examples of stereoselective Reformatsky type reactions which delineate the present state of the art are summarized in Scheme 14.6. 

Scheme 14.6 Selected examples of stereoselective Reformatsky reactions.

As mentioned in Section 7.2, when the electron transfer reaction between electron-rich alkenes and excited carbonyl compounds is energetically favorable, the RI pair becomes an important intermediate in photochemical [2 + 2] cycloaddition reactions (Scheme 7.5). The regioselectivity of these reactions may differ from that observed for the PB reaction involving 1,4-triplet biradical intermediates. Typical examples of PB reactions with very electron-rich alkenes, ketene silyl acetals (Eox = 0.9 V vs SCE), have been reported (Scheme 7.11) [27]. Thus, 2-alkoxyoxetanes were selectively formed as a result of the PB reaction with benzaldehyde or benzophenone derivatives, whereas a selective formation of 3-alkoxyoxetanes was observed in less electron-rich alkenes (see Scheme 7.9). When p-methoxybenzalde-hyde was used in the photochemical reaction, the regioselectivity was less than that observed in the case of benzaldehyde. This dramatic decrease in regioselectivity provided evidence that the selective formation of 2-alkoxyoxetanes occurred via RI pair intermediates. It should be noted that the stereoselectivity is also completely different from that associated with triplet 1,4-biradicals (vide infra). 

The stereochemical outcome of a photochemical [2 + 2] photocycloaddition depends highly on the approach of the two reactants as well as the sterochemical features of the product(s). In this context stereoselective [2 + 2]-photocycloaddition reactions have emerged as powerful C-C bond forming transformations leading to useful and versatile building blocks [59,60]. Some examples of such reactions are presented below. 

---