Kinetic control diastereoselective protonation

A diastereoselective route to d.v-2,3-disubstituted cyclohexanones is based on the kinetically controlled protonation of the enolate obtained via the addition of an arylacetonitrile to 2-sub-stituted 2-cycloalkenones in THF or in THF/HMPA mixtures at — 70-0 °C 299,30°, see also refs 301, 302 and 403. 

Diastereoselective protonation under kinetic control is a useful strategy for allowing access to particular diastereoisomeric carbonyl derivatives. For example, deprotonation of y-lactone 116 with excess LiHMDS in THF at —78°C, and quenching the resulting lithium enolate with saturated aqueous solution of sodium sulfate, gave the diastereoiso-mericaUy pure y-lactone 116 (equation 27). The diastereoselective protonation of the intermediate hthium enolate with H2O must occur on its less hindered face, controlled by the y-benzyloxymethyl substituent of the y-lactone residue to give the required 116. ... 

In many cases various proton sources, solvents, auxiliaries, and conditions have been applied in order to obtain different diastereoselectivites from the protonation of nonstereogenic car-banion centers. However, only the tw o extreme diastereomeric product ratios are given in this section. In most experiments kinetically controlled protonation can be assumed. However, since the anionic substrate already carries one (or more) stereogenic center, selective equilibration at the newly formed stereogenic carbon - hydrogen center could increase the diastereoselec-tivity. Indeed, epimerization of this center is a valuable tool for diastereoselective synthesis, provided that the carbon-hydrogen bond is acidic enough (see enolates, Section 2.1.3.1). 

The resulting nucleophilic alkoxymethyl radical may be trapped by an electron-deficient alkene. Reduction of the adduct radical (3 by DCA radical anion and protonation of the resulting anion, confirmed by deuterium incorporation from methanol-OD, gives the final product (3%). The diastereoselectivity shown has its origin in a preference for protonation, under kinetic control, from the less hindered side. For acyclic alkenes such as methyl 2-cyanocrotonate or dimethyl maleate, free rotation within (395) results in a low cisJrans ratio of 1.8-2.5 1 whereas for cyclic alkenes such as N,3-dimethylmaleimide or 3-methylmaleimide the cisitrans ratio is considerably higher at 86 14. ... 

The rate of epimerization of an a-stereogenic centre within a carbonyl-containing compound with several stereogenic centres depends on the acidity of the enolizable proton. Diastereoselectivity depends on kinetic and/or thermodynamic effects (reagent and substrate control)... 

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