Alkylations of metal enolates

Considerable attention was given to the stereochemistry for the alkylation of metal enolates of y-butyrolactones during the past 1980 s decade. It is well recognized that electrophihc attack on the enolates of -substituted y-butyrolactones is controlled exclusively by the -substituent leading to the trans addition products . However, Iwasaki and coworkers reported the reverse diastereofacial differentiation in the alkylation of the enolates of a, S-dibenzyl-y-butyrolactones. These authors proposed that the factor controlling the selectivity in this case was allylic strain. Also, y-substituted y-lactones give stereoselective trans alkylation . ... 

ALKYLATIONS OF METAL ENOLATES OF CARBOXYUC ACID DERIVATIVES... 

This chapter will provide coverage of the scope and limitations of alkylations of metal enolates of saturated and unsaturated ketones, aldehydes and carboxylic acid derivatives, together with a discussion of alkylations of various enols and enolate equivalents. Where applicable, the utility of these reactions for the diastereoselective and enantioselective synthesis of a-substituted carbonyl compounds will be described. Inevitably, the coverage of a vast research area such as this will be incomplete and in part will reflect the author s interests. However, it is hoped that most of the useful methods of carbon-carbon o-bond formation by alkylations of enolates and enols will be included. 

Existing evidence indicates that C-alkylations of metal enolates with common electrophiles proceeds by an SN2-type mechanism that is, the highest occupied molecular orbital (HOMO) of the enolate attacks the lowest unoccupied molecular orbital (LUMO) of the alkylating agent. Scheme 16 illustrates the principle of stereoelectronic control, which states that the electrophile should approach in a plane perpendicular to the enolate to allow maintenance of maximum orbital overlap in the transition state (24) between the developing C—C bond and the ir-orbital of the carbonyl group. 

In recent years, investigations of the diastereoselectivity and enantioselectivity of alkylations of metal enolates of carboxylic acid derivatives have become one of the most active areas of research in synthetic organic chemistry. Intraannular, extraannular and chelate-enforced intraannular chirality transfer may be involved in determining the stereochemistry of these alkylations. 

The alkylation of metal enolates ranks among the most powerful asymmetric C-C bond-forming reactions in the arsenal of organic transformations. Their pivotal utility in the synthesis of complex molecules stems from the predictability, reliability, and - importantly - ease of execution of these process in the laboratory. Numerous contributions to the field clearly demonstrate that research in this area continues to provide handsome dividends in the form of new, powerful tools for asymmetric C-C bond construction. 

The effect of crown ethers on the rates and stereochemistry of the alkylation of metal acetoacetates has been studied by Cambillau et al. (1976, 1978) and Kurts et al. (1973, 1974). Since the enolate can adopt various conformations ([96]—[99]), O-alkylation may produce either the cis ([100]) or the trans ([101]) isomer, whereas C-alkylation affords [102]. The reaction of the sodium... 

A method for enantioselective synthesis of carboxylic acid derivatives is based on alkylation of the enolates of /V-acyl oxazolidinones.59 The lithium enolates have the structures shown because of the tendency for the metal cation to form a chelate. 

An extension of the carbozincation of unactivated olefins by zinc enamides was recently reported and opened a new efficient entry to -alkylated ketones, especially those bearing an -secondary or tertiary alkyl group289. Indeed, such substrates are difficult to obtain by the conventional method relying on the alkylation of metal enamides or enolates... 

The Novartis Institute for BioMedical Research in Basel, Switzerland, and the University of Hull, UK, performed the diastereoselective alkylation of metal-stabilized enolates using a pressure-driven microreactor at — 100°C, whereby increased conversions and diastereoselectivity were observed compared to the batch process [20]. 

Chemistry of the Alkaline Earth Metal Enolates Alkylation of Ester Enolates... 

The fluorination of carbonyl compounds is facilitated by the formation of a metal enolate prior to fluorination. The fluorination of metal enolates has been successfully achieved using a wide variety of N-F reagents, e.g. A-fluorosulfonamidcs, chiral /V-fluorocamphorsul-tam." A-fluorooxathiazinone dioxides," iV-fluoroperfluoroalkylsulfonamides." 1-fluoropyridinium trifluoromethanesulfonates, " and l-alkyl-4-fluoro-1,4-dia7-oniabicyclo[2.2.2]octane salts" (see Table 8). 

Mechanism Because the Tr-electron systems of the two functional groups in a,p-unsaturated ketone are conjugated, the radical anion A formed by electron addition from a reducing metal is resonance stabilized. The usual fate of the A is protonation (or other electrophilic bonding) at the P-carbon atom. This creates an enoxy radical B which immediately accepts an electron to form an enolate anion C. Protonation or alkylation of this enolate species then gives a saturated ketone D or E, which may be isolated or further reduced depending on the reaction conditions (Scheme 6.33). 

When competing Claisen condensation of the ester is a problem, the use of the sterically hindered t-butyl esters is recommended. Unlike with ketone enolates, the 0-alkylation of ester enolates generally is not a problem. Consequently, HMPA may be added to ester enolate alkylations to improve yields. Many S 2 reactions proceed more readily in HMPA than in THF, DME, or DMSO. A solvent for replacing the carcinogenic HMPA in a variety of alkylation reactions is l,3-dimethyl-3,4,5,6-tetrahy-dro-2(lH)pyrimidinone (A,A -dimethylpropyleneurea, DMPU), which also has a strong dipole to facilitate metal counterion coordination. ... 

The formation and further transformation of esters belongs to the fundamentals of organic chemistry. Moreover, some esters have enormous importance for example triglycerides (1), in the form of fats and oils, are produced in million ton quantities for a number of applications. Other esters, e.g. (2) and (3), are olifactory components waxes, e.g. (4), are used commercially to protect metallic surfaces against corrosion. Aspartame (5) is an important artificial sweetener, and pyrethrin (6) is the prototype of the pyre-throids, an unusually potent class of insecticides. Apart from these more applied considerations, esters are important synthetic intermediates in a number of multistep sequences. Striking examples are chain elongations via Homer alkenation or a-alkylations of ester enolates, in particular the ones stereocon-trolled by chiral auxiliaries. ... 

Alkylations of acyclic enolates containing a collection of chiral auxiliary groups have been used successfully for the asymmetric synthesis of carboxylic acids. The chiral, nonracemic substrates that have been used include amides, imides, esters, imine derivatives of glycinates and acyl derivatives of chiral transition metals. In these systems either extraannular or chelate-enforced intraannular chirality transfer may control the sense of the alkylation step. 

Using palladium metal complexed with chiral Hgands, allylic alkylations of stabilized enolates have been developed in recent years into highly enantioselective... 

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