Kinetic control 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. 

Tetraphenylcyclopent-3-enone and dimethyl phosphonate are the major products from the base-catalysed reaction of methyl phosphonate with tetra-cyclone.75 A mechanism involving initial hydride transfer from dimethyl phosphinate anion to the ketone followed by kinetically controlled protonation to give (98) is suggested. 

The kinetically controlled protonation method may also be applied to the determination of the conformational free energy of C-methyl groups in piperidines. For example, protonation of 1,5-dimethylpiperidine (in which 13C is located in the /V-CH3 group) in dodecane and estimation of the ions produced by 13C-NMR spectroscopy gives AG20° of 1.5 0.1 kcal mol-1 for the 3-methyl group.169... 

The double bond shift is explained in terms of a kinetically controlled protonation of the anion formed in an ECE process the anion would have the highest negative charge a to the ester group. Such a double bond shift seems to be rather general also for the indirect reduction of allyl alcohols.388... 

Circular dichroism as well as dipole moments have been used only rarely for the elucidation of the conformation of indolizidines. It was claimed that the rate of methylation and the configuration of salts formed by protonation reflects the conformation of the free bases (79RCR262). There is an interesting new method depending on the kinetically controlled protonation of amines (77T915) which apparently has not been applied to indolizidines so far. 

Monoacetates of the corticosteroid dihydroxyacetone side-chain are not ordinarily accessible because of their propensity for acetyl migration to C-21. Hydrolysis of the 17,21-orthoacetate (119) in a phthalate buffer at pH 3, however, gave the 17-acetate (120) in high yield,presumably through kinetically-controlled protonation at the more-exposed C-21 oxygen atom. 

If stereoselectivity is to be achieved by a kinetically controlled protonation, product equilibration must be strictly suppressed. Therefore, the acidity of the resulting protonated compound should be 4-6 pA -units less than that of the proton sourees applied. For example, if protonation is achieved by an alcohol fpKa 16), the pKa of the newly formed carbon hydrogen bond should be not less than 20. In addition, the product must be isolated under conditions which avoid equilibration. 

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). 

A further example is the contrathermodynamic isomerization of e.w-3,6,6-trimethylbicy-clo[3.1.1]heptan-2-one to the eWo-isomer. The e.vo-isomer is first converted to the enamine. Kinetically controlled protonation furnishes the e.vo-salt which isomerizes quantitatively to the endo-isomer on standing. Final hydrolysis then gives the endo-ketone 2132. 

To our mind, the enolate of 19 should exhibit a decided kinetic bias for kinetically controlled protonation on its a face because of the steric encumbrance associated with p proton delivery. In actual fact, rapid introduction of its lithium salt into a 1 4 mixture of water and tetrahydrofuran at -78 °C resulted in its quantitative conversion to 20 (Scheme III). Once the MOM groups had been removed, controlled oxidation with manganese dioxide led to 21, a very pivotal intermediate. To arrive at magellaninone (2), 21 was treated with methyllithium and the resulting unprotected diol 22 was directly reduced with lithium aluminum hydride. Subsequent Jones oxidation proceeded with the customary allylic rearrangement. 

Enolate anions with extended conjugation can be formed by proton abstraction of a,p-unsaturated carbonyl compounds (1.9). Kinetically controlled alkylation of the delocalized anion takes place at the a-carbon atom to give the p,7-unsaturated compound directly. A similar course is followed in the kinetically controlled protonation of such anions. 

Prochiral enolates possess two enantiotopic sides, so that the kinetically controlled proton transfer leads selectively to a single enantiomer (priority for(R)/(S) and (E)/(Z) Ri rge > Usman > test of the molecule). 

This may be explained by the favourable steric conditions for reaction of the base with the carbonyl function of the 4-methyl-3-pentenoyl side chain, which in cis isohumulone is in the trans position relative to the vicinal 3-methyl-2-butenyl side chain. Through a retro carbanion addition to the carbonyl group a stabilized carbanion is generated at C-4. Inversion should occur smoothly giving a cis-trans mixture of humulinic acids in a ratio of 7 3 by a kinetically controlled protonation. 

The planned utilization of (A) involved deconjugatjpn, by kinetically controlled protonation of the enolate of (A), to give the desired -piperideine. Instead, a product (C) derived, formally at least, by cyclization of the immonium species (B) on the indole nitrogen was produced. However, this product could be converted to the dasycarpidone nucleus by treatment with aqueous acetic acid. 

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