Chelation directed addition

The first one is substrate controlled and can be used to split aUyUc ethers via the chelate-directed addition of a Grignard reagent (see 347). The process is absolutely regio- and stereoselective as 348 documents. 

Zinc acetate catalyst produces essentially 100% o-methylol phenol (8) in the first step. The second step gives an approximately equal quantity of 2,2 -(5, 45%) and 2,4 -diphenyhnethylene (6, 45%) bridges, indicating Htde chelate-directing influence. In addition, a small quantity (10%) of methylene ether units (9) (diben2yl ether) is observed at moderate reaction temperature. 

In contrast to the results obtained with the jS-alkoxy-a-alkyl-y-lactol 16 (vide supra), a chelation-directed, anti-Cram selective nucleophilic addition to the a-methyl-y-lactol 1 was not only observed with methyllithium and methylmagnesium bromide but also with (triisopropoxy)methyl-titanium72. In fact, the highest diastereoselectivity (> 98 % de) was observed with the titanium reagent in dichloromethane as reaction solvent. A seven-membered chelate 3 with the a-methyl substituent in a pscudoequatorial position has been postulated in order to explain the stereochemical outcome. 

Additional publications from Sanford et al. describe the full exploration of palladium-catalyzed chelate-directed chlorination, bromination, and iodination of arenes using N-halosuccinimides as the terminal oxidant <06T11483>. Moreover, an electrophilic fluorination of dihalopyridine-4-carboxaldehydes was reported by Shin et al. <06JFC755>. This was accomplished via transmetalation of the bromo derivative, followed by treatment with A-fluorobenzenesulfinimide as the source of electrophilic fluorine. 

A typical batch procedure involves direct addition of one part Chelex to four parts buffer solution (weight/ volume) with subsequent filtration to remove the resin. This treatment will readily remove iron, copper, zinc, calcium, and magnesium ions. Optimal chelation for iron and calcium ions occurs at pH 5-6.4 for copper, zinc, and magnesium ions, the optimal pH range is 7.4-8.0. 

When the cation remains coordinated to the nucleophile, the reaction is under association control. Association-controlled reactions are usually slow, because the substrate is not activated and the nucleophile is deactivated. This general class can be subdivided into two groups. In the first (which occurs in the C-alkylation of enolates), the metal is not directly bound to the reactive site. If the transition state is acyclic, conjugate additions will dominate because there is no electrophilic assistance. If it is cyclic, chelation favors addition to the carbonyl ... 

Despite the great deal of attention devoted to nucleophilic additions to a-chiral carbonyls, the source of stereoselectivity in these reactions (predicted by Cram s rules of asymmetric induction ) remains largely unresolved. Neither direct structural studies nor correlation of reactant and product stereochemistries have yielded any conclusive support for a single comprehensive model. Similarly, the effect of Lewis acids on these systems is only understood at the level of chelation-controlled additions (vide infra). 

The authors surmise that the trichlorostannyl intermediate 218 directs a chelation-controlled addition via 220, which may involve pseudo-axial complexation of the carbamate carbonyl. The stereoselectivity of the allylation is significantly altered by the use of 2.0 equivalents of SnCU to produce the corresponding i yn.i yn-isomer of 219 via the antiperiplanar transition state derived from the a-chelation model for addition of y-alkoxyallylstannanes. 

The addition methodology was also shown to be successful with aldehydes and A -acylinunes, by altering the nature of the silyl residue on the allene 7. a-AIkoxy aldehydes exert a very strong directing influence on this addition, as shown by the following transformation, which occurs via chelation-controlled addition. 

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