Controlling group, stereoselectivity

Spatial and/or coordinative bias can be introduced into a reaction substrate by coupling it to an auxiliary or controller group, which may be achiral or chiral. The use of chiral controller groups is often used to generate enantioselectively the initial stereocenters in a multistep synthetic sequence leading to a stereochemically complex molecule. Some examples of the application of controller groups to achieve stereoselectivity are shown retrosynthetically in Chart 19. 

The best known of metal carbene reactions, cydopropanation reactions, have been used since the earliest days of diazo chemistry for addition reactions to the carbon-carbon double bond. Electron-donating groups (EDG) on the carbon-carbon double bond facilitate this catalytic reaction [37], whereas electron-withdrawing groups (EWG) inhibit addition while facilitating noncatalytic dipolar cycloaddition of the diazo compound [39] (Scheme 5). There are several reviews that describe the earlier synthetic approaches [1, 2,4, 5,40-43], and these will not be duplicated here. Focus will be given in this review to control of stereoselectivity. 

Chelation Control. The stereoselectivity of reduction of carbonyl groups can be controlled by chelation when there is a nearby donor substituent. In the presence of such a group, specific complexation among the substituent, the carbonyl oxygen, and the Lewis acid can establish a preferred conformation for the reactant. Usually hydride is then delivered from the less sterically hindered face of the chelate so the hydroxy group is anti to the chelating substituent. 

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 ... 

The two-steps synthesis of thiophosphorylated cavitands is by far the best method to control the stereoselectivity of the resultant products. As for the P=0 partners, it is important to obtain the all-inward oriented P=S donating groups in high yields to benefit from cooperative effects of the P=S donor groups and the aromatic cavity in the formation of host-guest complexes. 

The 1,3-dipolar cycloadditions of 1,3-dipoles with chiral alkenes has been extensively reviewed and thus only selected examples will be highlighted here. We have chosen to divide this section on the basis of the different types of alkenes rather than on the basis of the type of 1,3-dipole. For 1,3-dipolar cycloadditions, as well as for other reactions, it is important that the chiral center intended to control the stereoselectivity of the reaction is located as close as possible to the functional group of the molecule at which the reaction takes place. Hence, alkenes bearing the chiral center vicinal to the double bond are most frequently apphed in asymmetric 1,3-dipolar cycloadditions. Examples of the application of alkenes with the chiral center localized two or more bonds apart from the alkene will also be mentioned. Application of chiral auxiliaries for alkenes is very common and will be described separately in Section 12.3. 

Coupling reactions of aldehydes or ketones to 1,2-diols proceed with low-valent metals such as magnesium, zinc, and aluminum.Because it is not easy to control the stereoselectivity (diastereoselectivity and/or enantioselectivity) of the reactions with such main group metals, low-valent species of early transition metals are frequently employed with electron-donating ligands. The representative reagents are low-valent titanium and samarium species. 

Claisen rearrangement.1 Allyl vinyl ethers such as 3 undergo Claisen rearrangement reluctantly and in low yield when treated with methylaluminum bis(2,6-di-f-butylphenoxide), MAD but this dibromo derivative, 1, effects this rearrangement readily at -78° with high (Z)-selectivity. Evidently the bulky r-butyl groups control the stereoselectivity, for use of methylaluminum bis(2,6-diphenylphenox-... 

However, a computational study124 shows that the Kishi model controls the stereoselectivity for (Z)-alkenes. Note also that in the Diels-Alder reactions of hexachloropentadiene with chiral alkenes, the inside alkoxy effect is attributed to electrostatic repulsion of the oxy group in the125 outside position with the chlorine atom of hexachloropentadiene in the 1-position. 

There has been considerable interest in the factors that control the stereoselectivity of cyclobutanol formation. Three main factors were identified quite early pre-existing conformational preferences due to steric effects or to internal hydrogen bonding solvation of the OH group and variable rotational barriers for cyclization. More recently Griesbeck has proposed that orbital orientation favoring soc produces another form of conformational preference in triplet biradicals [55], These factors have different importance depending upon the molecule. 

A remote sulfinyl group has also been used to control the stereoselectivity of the hetero-Diels-Alder reaction of the carbonyl group of furfural [176]. Reaction of sulfoxide 236 with Danishefsky s diene in the presence of Ln(OTf)3 (Ln = Yb, Nd, and Sm) yielded cycloadducts 237a and 237b with high de (93-99%). When reactions were conducted under Eu(thd)3 catalysis, the stereoselectivity of the reaction was dramatically inverted (Scheme 107). The influence of the catalysts in the stereoselectivity is not discussed. 

BBN attacks the C=C double bond of 3-ethyl-l-methylcyclohexene according to Figure 3.20 exclusively from the side that lies opposite the ethyl group at the stereocenter. Consequently, after oxidation and hydrolysis, a fra s,fra s-configured alcohol is produced. The question that arises is Can this diastereoselectivity be reversed in favor of the cis,trans isomer The answer is possibly, but, if so, only by using reagent control of stereoselectivity (cf. Section 3.4.4). 

Chiral enolates can be made from compounds with a stereogenic centre 3 to a carbonyl group. Once the carbonyl is deprotonated to form the enolate, the stereogenic centre is next to the double bond and in a position to control the stereoselectivity of its reactions, The scheme below shows stereoselectivity in the reactions of some chiral enolates with methyl iodide. 

In 1978, Larcheveque and coworkers reported modest yields and diastereoselectivities in alkylations of enolates of (-)-ephedrine amides. However, two years later, Evans and Takacs and Sonnet and Heath reported simultaneously that amides derived from (S)-prolinol were much more suitable substrates for such reactions. Deprotonations of these amides with LDA in the THF gave (Z)-enolates (due to allylic strain that would be associated with ( )-enolate formation) and the stereochemical outcome of the alkylation step was rationalized by assuming that the reagent approached preferentially from the less-hindered Jt-face of a chelated species such as (133 Scheme 62). When the hydroxy group of the starting prolinol amide was protected by conversion into various ether derivatives, alkylations of the corresponding lithium enolates were re-face selective. Apparently, in these cases steric factors rather than chelation effects controlled the stereoselectivity of the alkylation. It is of interest to note that enolates such as (133) are attached primarily from the 5/-face by terminal epoxides. ... 

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