Factors that influence stereoselectivity

If stereoisomerism is possible, the Wittig reaction generally produces (F/Z)-isomeric mixtures. The stereoselectivity of olefination depends on a number of factors  

As many parameters influence the ( /Zj-ratio, it is difficult to predict the stereochemical course of a Wittig reaction. Nevertheless, some basic rules have been worked out [6,19,20]. Reactive ylides in apolar solvents such as benzene or ether preferentially form the thermodynamically less stable (Zj-isomer, in particular under so-called salt-free conditions, i.e. when no soluble lithium salts are present in the reaction mixture. In the presence of LiX, the proportion of (Fj-isomer increases in the order X = Cl Br I BPh4 [20]. In polar aprotic 

Stable ylides show the opposite behaviour. In polar and apolar media they lead to the thermodynamically stable f j-isomer, frequently with virtually no formation of the fZj-isomer. The stereoselectivity is not influenced by soluble lithium salts. 

Semi-stable ylides generally exhibit no great steric preference, although there is a slight tendency towards f )-selectivity. In apolar solvents the presence of soluble lithium salts seems to give a trend towards a slight increase in the proportion of (Z)-isomer [20]. 

In carotenoid synthesis, semi-stable ylides are generally employed, frequently in polar protic or aprotic solvents or solvent systems. 

---

The purpose of this review is to provide a summary (through to the end of 1988) of the uncatalyzed reactions of type I and type III allyl organometallics with C X electrophiles. Most of the examples involve aldehydes and ketones, but the reactions of allyl organometallics with imines are also covered. Because the focus of this review is on selectivity and synthetic efficiency, this review is not intended to be as comprehensive as an Organic Reactions chapter or a Chemical Reviews article. Rather, we have attempted to define and illustrate the factors that influence stereoselectivity, to provide access to the most pertinent literature, and, most importantly, to provide a basis for selection of an allyl organometallic reagent for application in specific synthetic problems. 

It is the primary goal of this book to analyze the factors that influence stereoselectivity when one stereoisomer predominates over others. For illustrative purposes, consider the addition of a nucleophile to a carbonyl. The faces of unsymmetric carbonyls are heterotopic, either enantiotopic (if there are no stereocenters in the molecule) or diastereotopic (if there are), as shown in Figure 1.1 (see also glossary. Section 1.6). In order to achieve a predominance of one stereoisomer (enantiomer or diastereomer) over the other, the transition states resulting from attack from the heterotopic Re or Si faces must be diastereomeric. This will be the case if either the carbonyl compound or the reagent (or both) is (are) chiral. 

Recent advances in the rhodium-catalyzed [4-1-2] reactions have led to the development of the first highly regioselective intermolecular cyclization, providing access to new classes of carbocycles with both activated and unactivated substrates. The chemo- and stereoselective carbocyclizations of tethered diene-allene derivatives afford new classes of 5,6- and 6,6-bicyclic systems. Additionally, examination of a wide range of factors that influence both diastereo- and enantioselectivity has provided a significant advance in the understanding of catalyst requirements across these systems. 

The remainder of this chapter will detail examples of the main types of Wittig reaction using examples to highlight (i) those factors that influence the stereoselectivity of the above methods, (ii) modifications to the standard procedures, and (iii) uses of these reactions in organic synthesis. 

To achieve control of stereochemistry, understanding is vital, and understanding requires a feeling for all the factors that influence the stereochemistry of organic reactions. We begin with two adjectives, stereoselective and stereospecific, which, with their derived adverbs, are much used and misused. They are defined following Zimmerman below, and used carefully in this book, because the distinction between them is useful. 

From these examples it is clear that the principles of acyclic stereocontrol that govern the allylation reactions of achiral Type II allyl- and crotylmetal reagents with chiral aldehydes can be used to excellent advantage in the stereoselective synthesis of natural products. In the following section, the factors that influence the stereoselective formation of cyclic compounds in the ring-closing allylation reaction are discussed and selected synthetic applications are reviewed. 

Some common factors that influence the stereochemical outcome of the HWE reaction are summarized in Table 1.2. In general, the addition of a phosphonate to a ketone occurs with moderate -selectivity [24]. The reaction of an a-substituted phosphonate with an aldehyde also usually favors the -alkene (Scheme 1.9), although some exceptions have been noted [25, 26]. The -selectivity is further enhanced with the use of large phosphoryl and carbanion substituents [27, 28]. However, a-substituted phosphonates that bear a large alkyl chain give only modest -seIectivity. a-Fluoro phosphonates are reported to provide impressive E- or Z-stereoselectivity (Scheme 1.10), which has been attributed to electronic effects [29]. 

Moderate stereoselectivity is also seen in the addition of phenoxycarbene to cyclohexene (enby 4), in which the product ratio is apparently influenced by steric factors that favor introduction of the larger group (PhO versus H) in the less crowded exo position. 

The regioselectivity and stereoselectivity of electrophilic additions to 2-benzyl-3-azabicyclo[2.2.1]hept-5-en-3-one are quite dependent on the specific electrophile. Discuss the factors that could influence the differing selectivity patterns that are observed. 

NU(C) base atoms (5) The stereoselectivity of the BPDEs during intercalative covalent binding in kinked DNA and (6) The possible reorientation of the complex to yield an externally bound adduct. The energetics for each of these processes will be presented to identify the important steps that influence the binding of specific isomers. It will be shown that the orientation of each diastereoisomer of BPDE about specific base atoms in kinked receptor sites in the duplex DNA during covalent bond formation is the determining factor in stereoselectivity. 

Factors which influence the stereoselectivity of organic reactions have been under intense investigation recently because of the increasing requirement and profitability of producing stereoisomerically pure compounds. A great deal of progress has been made, but even more remains to be accomplished. The specific contributors to stereoselectivity in individual reactions will be discussed as they are encountered. At this point it is important to be aware of the stereochemical variations that are possible. 

The focus of this chapter is on the stereoselectivity of the conjugate addition of the Lewis acid and enamine Michael additions. Only donors that are formally enol equivalents are considered. Selectivity that results from preferential addition to one of the faces of an endocyclic enamine or enol ether as a result of the influence of a stereocenter in the ring is not emphasized. In general, the factors that control the stereochemistry in these instances are analogous to those active in the reactions of other electrophiles with such compounds. 

It is also important to note that several factors influence both the stereoselectivity of hydrogen exchange and enolate formation in base-promoted reactions. Houk, Ando and co-workers found that differing conju-gative stabilization by CH p-orbital overlap does not directly influence stereoselectivity.205 Steric effects only dominate is exceptionally crowded transition structures, but torsional strain involving vicinal bonds contributes significantly to the stereoselectivity of all cases studied. 

One factor that the mechanistic scheme does not address is the change in stereoselectivity observed for the reaction of o-iodoanilides upon the addition of silver salts (Scheme 12.8). Recently, the influence of additives on the enantioselective intramolecular Mizoroki-Heck reaction of o-iodoaniUde 39 was studied in a series of reactions in which reaction times, temperatures, concentration and catalyst/Ag3P04 loading were varied [19]. It was observed that, in the presence of Ag3P04, the enantioselectivity of the product 40 increased... 

It is known that many factors can influence the stereochemical outcome of the Wittig reaction. Although this reaction frequently leads to mixtures of stereoisomers by suitable choice of reagants and reaction conditions, the reaction can be made stereoselective. 

---