Direct Alkylation of Simple Enolates

To obviate 0-alkylation, the readily accessible l,5-dimethoxy-l,4-cyclohexa-diene surrogate derived from Birch reduction of 1,3-dimethoxybenzene can be used. Enol ether hydrolysis affords the alkylated 1,3-cyclohexadiones in excellent yields.  

0-Alkylation may occur when the enolate anion and its counteranion are dissociated. Shielding of the enolate by the cation represses 0-alkylation. The tendency of cations to dissociate from oxygen follows the trend R4N Na Li. The selec- 

Esters (pAT 25) do not form high concentration of enolates when treated with alkox-ides (alcohol 16-18). Therefore, strong, non-nucleophilic bases, such as EDA (i-Pr2NH pK. = 36), are required to rapidly and quantitatively deprotonate them at -78 °C in THF. The ester is added to a solution of LDA in Et20 or in THF (inverse addition). After the ester enolate is completely formed under these kinetic conditions, 

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.  

If the ester possesses a (3-stereocenter and the P-substituents are of widely different steric size, then alkylation of the enolate derived from such an ester usually leads to high diastereoselectivity. In the example shown below, to minimize the A strain the enolate adopts a conformation in which the smallest group (H) is nearly eclipsing with the double bond. The electrophile, Mel, then approaches the enolate from the side opposite the larger group (PhMejSi). 

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The. V-alkylation of ephedrine is a convenient method for obtaining tertiary amines which are useful as catalysts, e.g., for enantioselective addition of zinc alkyls to carbonyl compounds (Section D. 1.3.1.4.), and as molybdenum complexes for enantioselective epoxidation of allylic alcohols (Section D.4.5.2.2.). As the lithium salts, they are used as chiral bases, and in the free form for the enantioselective protonation of enolates (Section D.2.I.). As auxiliaries, such tertiary amines were used for electrophilic amination (Section D.7.I.), and carbanionic reactions, e.g., Michael additions (Sections D. 1.5.2.1. and D.1.5.2.4.). For the introduction of simple jV-substituents (CH3, F.t, I-Pr, Pretc.), reductive amination of the corresponding carbonyl compounds with Raney nickel is the method of choice13. For /V-substituents containing further functional groups, e.g., 6 and 7, direct alkylations of ephedrine and pseudoephedrine have both been applied14,15. 

Li s copper-catalyzed oxidative difunctionalization of enol ethers with a-amino carbonyl compounds was recently reported (Scheme 2.9) [41]. This protocol allows rapid synthesis of 2-amino-3,4-dioxy carbonyl products. Significantly, metal-fiee, DTBP-mediated direct alkylation of a-amino carbonyl compounds with C—H bond of simple alkanes was developed by Cheng and co-workers [42]. 

The synthetic problem is now reduced to cyclopentanone 16. This substance possesses two stereocenters, one of which is quaternary, and its constitution permits a productive retrosynthetic maneuver. Retrosynthetic disassembly of 16 by cleavage of the indicated bond furnishes compounds 17 and 18 as potential precursors. In the synthetic direction, a diastereoselective alkylation of the thermodynamic (more substituted) enolate derived from 18 with alkyl iodide 17 could afford intermediate 16. While trimethylsilyl enol ether 18 could arise through silylation of the enolate oxygen produced by a Michael addition of a divinyl cuprate reagent to 2-methylcyclopentenone (19), iodide 17 can be traced to the simple and readily available building blocks 7 and 20. The application of this basic plan to a synthesis of racemic estrone [( >1] is described below. 

Since fluoro-carbonyl compounds are such useful and versatile synthetic intermediates, much effort has been devoted to their preparation [124], but only in a few instances has elemental fluorine been used directly. One of the earliest successful direct fluorinations of a simple carbonyl compound was the fluorina-tion of pyruvic acid derivatives which have a high enol content (R = Aryl, Acyl) (Fig. 47) [125] in the solvent being used (mixtures of CF2C1CFC12 and acetonitrile). However, in derivatives where the enol content was low (R = Alkyl), complicated mixtures of products were obtained. 

In contrast, /3-dicarbonyl compounds such as malonic ester and acetoacetic ester are more acidic than alcohols. They are completely deprotonated by alkoxides, and the resulting enolates are easily alkylated and acylated. At the end of the synthesis, one of the carbonyl groups can be removed by decarboxylation, leaving a compound that is difficult or impossible to make by direct alkylation or acylation of a simple ester. 

Prior to the advent of organocatalysis, the asymmetric direct a-allqtlation reaction was relatively unknown. Classical methods to access a-allq lated carbonyl products required stoichiometric amounts of preformed aldehyde metal enolates. Additionally, side reactions such as aldol, Canizzaro- or Tischenko-type processes diminished the efficiency of these reactions. In this sense the asymmetric intermolecular Sjj2 a-alkylation of aldehydes with simple allq l halides has been a difficult feat to achieve. 

If the substituents are nonpolar, such as an alkyl or aryl group, the control is exerted mainly by steric effects. In particular, for a-substituted aldehydes, the Felkin TS model can be taken as the starting point for analysis, in combination with the cyclic TS. (See Section 2.4.1.3, Part A to review the Felkin model.) The analysis and prediction of the direction of the preferred reaction depends on the same principles as for simple diastereoselectivity and are done by consideration of the attractive and repulsive interactions in the presumed TS. In the Felkin model for nucleophilic addition to carbonyl centers the larger a-substituent is aligned anti to the approaching enolate and yields the 3,4-syn product. If reaction occurs by an alternative approach, the stereochemistry is reversed, and this is called an anti-Felkin approach. 

In the context of total synthesis, the reduction in the level of functionalization implicit in these processes is not always at variance with synthetic objectives, a simple example being the aldol condensation-deoxygenation sequence of Scheme 1, which could replace a (frequently more difficult) direct enolate alkylation. The conversion of readily available, polyfunctionalized materials such as carbohydrates into specifically deoxygenated or deaminated derivatives provides a variety of chiral synthons for the assembly of more complex substances. 

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