Stereoselectivity, in electrophilic reactions

The interpretation of the basis for this stereoselectivity can be made in terms of the steric, torsional, and stereoelectronic effects discussed in connection with reduction by hydrides. It has been found that crown ethers enhance stereoselectivity in the reaction of both Grignard reagents and alkyllithium compounds.119 This effect was attributed to decreased electrophilicity of the metal cations in the presence of the crown ether. The attenuated reactivity leads to greater selectivity. 

In 1999, the group of Lygo reported that the use of N-anthracenylmethyl-dihydrocinchonidinium chloride (6e) significantly improved the enantioselectivity of the alkylations with substituted benzyl bromides, enhancing the utility of this approach to a,a-dialkyl-a-amino acids [30]. For reproducible results, the mixed solid base KOH/K2CO3 must be freshly prepared before use. The lack of stereoselectivity in the reactions with other electrophiles was ascribed to competing, non-selective background alkylation (Scheme 2.10). 

Silica gel is also the support of choice for the activation of V-halosuccinimides. The silica functions both as a proton donor which increases the electrophilic nature of the reagent, and as a support with geometrical constraints which contributes to the stereoselectivity. Alkyl and aryl sulfoxides are readily halogenated at the a position with yields of48-80%91. The reactions are carried in the solid state on the surface of TLC plates. The conversion of the optically active alkyl 4-methylphenyl sulfoxide into 1-haloalkyl 4-methylphenyl sulfoxide is accompanied by inversion of configuration at the S-atom. The stereoselectivity in these reactions is much higher than that observed in liquid-phase halogenation. 

HO . The orientation of the approach of the nucleophile determines the ratio of cis and trans isomers in the resulting mixture, (147 + 149) (148 + 150). In actuality, electrophilic addition of Br" is directed almost exclusively at C-2 and hence products 147 and 148 are formed preferentially. While the ratio of these isomers is very sensitive to the reaction conditions, it is rather difficult to achieve a high stereoselectivity in the reaction and hence this method cannot be recommended for the preparation of the pure stereoisomers 147 or 148. 

In non-polar solvents a decrease in yield was observed in the reactions with N-bromosuccinimide, and a loss of stereoselectivity in the reaction of the exo-isomer with bromine. The inversion of configuration in the reaction with N-bromosuccinimide was explained by direct electrophilic displacement (Scheme 5), but the reaction with bromine was considered to proceed by an initial electron-transfer step, followed by nucleophilic attack of bromide ion on the resulting organopentafluorosilicate radical-ion (Scheme 6). Steric constraints or a reduction in the polarity of the solvent would allow dissociation of the radical ion to a free alkyl radical, and loss of stereoselectivity, as observed (Scheme 7). 

The Rubottom oxidation has found widespread application in organic synthesis. A few recent examples of the use of this methodology for the construction of complex molecules are described below. As noted above, the stereoselectivity in these reactions is usually controlled by steric effects, which dictate the face-selectivity of the epoxidation step. The chemoselectivity is generally controlled by electronic effects, as the electrophilic oxidants react more rapidly with the electron-rich enol ether than with other double bonds in the substrate. 

The direct asymmetric conjugate addition of simple aldehydes to electrophiles is crucial in organic reactions. Barbas et al. developed the first example of a highly stereoselective direct Michael reaction that involved adding unmodified aldehydes to nitro-olefins. After various p3Trolidine-diamines were screened, (S)-2-(morpholinomethyl)pyrrolidine Ic was determined to be the ideal catalyst for obtaining satisfactory stereoselectivity in the reaction. These reactions afforded various 2,3-disubstituted y-formyl nitroalkanes with satisfactory yields and moderate to good enantioselectivity (Scheme 9.12). ... 

Pyramidalization was explored as a direct stereoelectronic source of stereoselectivity in enamine reactions. Seebach and coworkers suggested that the remarkable stereoselectivity of pyrrolidino-enamines derived from proline in reactions with electrophiles originates from stereoelectronic assistance from the lone pair of pyramidalized enamine N-atoms (Figure 6.124). ° ... 

Sauer, G., Schrotei B. and Kiinzei H. (1988b) Striking influence of the reaction conditions on the stereoselectivity in electrophilic substitution of a 10-lithioergolinyl-urea. Tetrahedron Lett., 29, 6429-6432. 

As is the case for aldol addition, chiral auxiliaries and catalysts can be used to control stereoselectivity in conjugate addition reactions. Oxazolidinone chiral auxiliaries have been used in both the nucleophilic and electrophilic components under Lewis acid-catalyzed conditions. (V-Acyloxazolidinones can be converted to nucleophilic titanium enolates with TiCl3(0-/-Pr).320... 

Ketenes are especially reactive in [2 + 2] cycloadditions and an important reason is that they offer a low degree of steric interaction in the TS. Another reason is the electrophilic character of the ketene LUMO. As discussed in Section 10.4 of Part A, there is a large net charge transfer from the alkene to the ketene, with bond formation at the ketene sp carbon mnning ahead of that at the sp2 carbon. The stereoselectivity of ketene cycloadditions is the result of steric effects in the TS. Minimization of interaction between the substituents R and R leads to a cyclobutanone in which these substituents are cis, which is the stereochemistry usually observed in these reactions. 

According to the stepwise electrophilic reaction mechanism, the differences in the stereochemistries of the products from the reactions of alkenes with cyclic 49 and acyclic 51 disulfonium dications can be explained by the larger rates of the intramolecular reactions. In the case of a cyclic dication, the carbocationic center in intermediate 94, which is formed as the result of initial attack by a S-S dication on a double C=C bond reacts with nucleophile intramolecularly, thus conserving the configuration of the substituents at the double bond. On the other hand, an acyclic dication undergoes transformation to two separate particles (95 and dimethylsulfide) with a consequent loss of stereoselectivity. Additional experiments with deuteretad alkenes confirm that reaction is not stereoselective, lending further support to the stepwise mechanism (Scheme 36).106... 

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