Control by Neighboring Groups

Smallest group aligned with ketone group 

If one of the groups on the alpha carbon contains a lone pair and can act as a Lewis base (e.g., -OH, -OR, or -NH2), that group can chelate with a Lewis acid or the counterion of the nucleophile. Nucleophilic attack of the resulting cyclic, coordinated species occurs at the less hindered face. 

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A very active area of research in S Ar chemishy is in the field of asymmehic synthesis. This chemistry involves a unique set of electrophiles—those in which a chiral environment must exist near the electrophilic reaction site. In most cases, these asymmetric synthetic reactions are accomplished with a chiral electrophile or a chiral catalyst (or counterion) in tight coordination to the electrophile. For example, Stadler and Bach used a chiral electrophile (36) in an S Ar reaction leading to the natural product (-)-podophyllotoxin 38 (Scheme 1.10) [31]. With planar sp carhocation centers, facial selectivity may be controlled by neighboring groups, in this case the adjacent vinyl group on the lactone 36. The Friedel-Crafts chemistry provides intermediate 37, which is then converted to (-)-podophyllotoxin (38) as a single enantiomer. 

Miller et al. [87,88] have described the synthesis of hyperbranched aromatic poly(ether-ketone)s based on monomers containing one phenolic group and two fluorides which were activated towards nucleophilic substitution by neighboring groups. The molecular weight and polydispersity of the formed po-ly(ether-ketone)s could be controlled by reaction conditions such as monomer concentration and temperature. The formed polymers had high solubility in common solvents such as THF. 

K. Kobayashi, T. Ishii, M. Okada, and C. Schuerch, Steric control in ring-opening polymerization of 1,6-anhydrogalactose derivatives by neighboring group participation,... 

Related 2,3-anhydrogulofuranosyl sulfoxides have been employed in the stereo-controlled synthesis of P-arabinofuranosides [370]. The epimeric a-arabinofurano-sides have also been synthesized by the sulfoxide method, with the aid of the neighboring-group participation [371,372]. 

In all cases, the initial addition to generate 520 was diastereospecific, that is, the isocyanate always adds to 519 from the face opposite to the 4-ethyl substituent of the oxazoline. In the cases wherein 521 was isolated (Entries 17-20 from Table 8.33), the stereochemistry of the two additional chiral centers from the secondary [2 + 2] cycloaddition was controlled by the chiral center formed during the initial reaction, that is, the isocyanate reacts with 520 from the opposite face of the neighboring Ri group. For Ri = H, R2 = Me, 519 reacted with an arylisocyanate (R3 = Ar) to give tricyclic adducts 521a and 521b as a 1.7 1 mixture of diaster-eomers (Entries 18-20). For Rj = Ph, R2 = Me, 519 reacted with phenylisocyanate... 

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