Regioselective enolate alkylation

Two consecutive enolate alkylations were utilized to generate the quaternary carbon atom (Scheme 38). Alcohol 238 was transformed into the protected hydroxy enone 244. Regioselective deprotonation at the a-position of the ketone 244 led to a cross-conjugated enolate that was alkylated with the allylic iodide 245. The vinyl silyl moiety in 245 represents a masked keto group [127]. The choice of the TBS protecting group for the hydroxyl group at of 244 was crucial in order to prevent the deprotonation at the y-posi-... 

The regioselectivity of alkylations of silyl dienol ethers has been studied87,88. These reactions favor y-alkylation products. In contrast, alkylations of the corresponding lithium enolates mainly occur in the a-position. Substituents on the silyl diene unit, as well as the substituents at the silicon, strongly influence the regioselectivity of the reaction87 91,... 

Similarly, the enamine salt 15 is obtained by lithiation of 14 (equation 5). In both cases the lower steric hindrance leads to higher stability of the enaminic system33 where the double bond is formed on the less substituted carbon. The Af-metalated enamines 11 and 15 are enolate analogs and their contribution to the respective tautomer mixture of the lithium salts of azomethine derivatives will be discussed below. Normant and coworkers34 also reported complete regioselectivity in alkylations of ketimines that are derived from methyl ketones. The base for this lithiation is an active dialkylamide—the product of reaction of metallic lithium with dialkylamine in benzene/HMPA. Under these conditions ( hyperbasic media ), the imine compound of methyl ketones 14 loses a proton from the methyl group and the lithium salt 15 reacts with various electrophiles or is oxidized with iodine to yield, after hydrolysis, 16 and 17, respectively (equation 5). 

In 1980 Trost and Keinan reported on allylic alkylations of tin enolates such as 33 catalyzed by tetrakis(triphenylphosphine)palladium (equation 12). The stannyl ethers led to a rapid and clean monoaUcylation with high regioselectivity. Thereby, alkylation generally occurred at the less substituted end of the allyl moiety with formation... 

Enolate equilibration and di- and poly-alkylation are the major side reactions, which lead to reduced yields of desired products in ketone alkylations. These processes occur as a result of equilibration of the starting enolate (or enolate mixture) with the neutral monoalkylation product(s) via proton transfer reactions. Polyalkylation may also occur when bases, in addition to the starting enolate, which are capable of deprotonating the monoalkylated ketone are present in the medium. With symmetrical ketones, e.g. cyclopentanone and cyclohexanone, the problem of regioselectivity does not arise. However, except under special conditions, polyalkylation occurs to a significant extent during enolate alkylations of more kinetically acidic ketones such as cyclobutanone, cyclopentanone and acyclic ketones, particularly methyl ketones. Polyalkylation is also a troublesome side reaction with less acidic ketones such as cyclohexanone. 

Prior to the discoveries that lithium and other less electropositive metal cations were valuable counterions for enolate alkylations, the Stork enamine reaction was introduced to overcome problems such as loss of regioselectivity and polyalkylation that plagued attempts to alkylate sodium or potassium enolates of ketones or aldehydes.Methods of synthesis of enamines by reactions of ketones and aldehydes with secondary amines have been thoroughly reviewed.Enamine alkylations are usually conducted in methanol, dioxane or acetonitrile. Enamines are ambident nucleophiles and C- and V-alkylations are usually competitive. Subsequent hydrolysis of the C-alkylated product (an iminium salt) yields an... 

These limitations include the ability to regioselectively form an enolate from an unsymmetrical ketone, polyalkylation via enolate equilibration, and the necessity to use simple electrophiles hinder both chiral and achiral enolate alkylations. Additionally, this alkylation usually requires specific enolate geometry for chirality of the product and since the origin of enatioselectivity is defined by a combination of enolate geometry and facial selectivity of the alkylation, chirality in this reaction is difficult while maintaining atom economical practices. 

In later applications of this concept, Birchs conditions were frequently replaced by the hydride donor L-selectride that also generates lithium enolates from enones. That, even in the case of cross-conjugated dienones, a regioselective enolate formation occurs based upon the different steric encumbrance at the termini of the carbon-carbon double bonds, has been demonstrated by formation and subsequent diastereoselective allylic alkylation of the lithium enolate 112 (Scheme 2.34) [128]. 

The SAMP/RAMP Method As early as 1976, azaenolates derived from A,A-dialkyl hydrazones were studied as an alternative to direct ketone and aldehyde enolate alkylations. These species were found to exhibit higher reactivity toward electrophiles, as well as better regioselectivity for C-alkylation than their parent carbonyl compounds. A,A-diaIkyl hydrazones are stable and are relatively easy to prepare, making them appealing from a practical point of view in comparison with imines and enamines, which can be difficult to form quantitatively and are hydrolytically unstable. Given these desirable attributes, Enders undertook the development of chiral nonrace-mic A,A-diaIkyl hydrazine auxiliaries for the asymmetric a-alkylation of ketones. The result of his efforts were (5)-and (R)-l-amino-2-methoxypyrrohdine hydrazine (1 and 2, respectively), now commonly known as the SAMP and RAMP auxiliaries, respectively (Figure 7.1). Over the years, the SAMP/RAMP method has come to be considered the state-of-the-art approach to asymmetric ketone... 

SCHEME 7.33. Regioselectivity of alkylation of Li-enolates derived from Al-acyl sultams. 

Low molecular mass enol esters (e.g. acetates H.O. House, 1965) or enol ethers (e.g. silyl ethers H.O. House, 1969) of ketones can be synthesized regioselectively and/or separated by distillation. Treatment with lithium alkyls converts them into the corresponding lithi-... 

Other methods for the regioselective SN2-opening of vinyloxiranes include intramolecular enolate addition for formation of cyclohexane systems [135, 136] and Friedel-Crafts alkylations [49, 137, 138]. 

Stable enolates such as diethyl malonate anions react with allyl sulfones (or acetates) in the presence of nickel complexes to give a mixture of the a- and /-product83. The regioselectivity is generally poor in the nickel-catalyzed reaction, but the molybdenum-catalyzed reaction is selective for alkylation at the more substituted allylic site, thereby creating a quaternary carbon center84. 

Ketone imine anions can also be alkylated. The prediction of the regioselectivity of lithioenamine formation is somewhat more complex than for the case of kinetic ketone enolate formation. One of the complicating factors is that there are two imine stereoisomers, each of which can give rise to two regioisomeric imine anions. The isomers in which the nitrogen substituent R is syn to the double bond are the more stable.114... 

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