Functionalizations of Enolates

Classics in Stereoselective Synthesis. Erick M. Carreira and Lisbet Kvaerno Copyright 2009 WILEY-VCH Verlag GmbH Co. KGaA, Weinheim ISBN 978-3-527-32452-1 (Hardcover) 

Solvent-dependent rates of alkylation [3]. N3 -r BuBr— BuNj + Br  

State structure 2 in which l,3- iiaxial interactions are minimized. In contrast, deprotonation with LDA in a solvent mixture consisting of HMPA and THF predominantly affords the cis-ester enolate 7 (7 6 = 84 16). This result is believed to be the consequence of the intervention of non-cyclic transition states [15, 36, 37]. 

Enolization of the corresponding amides strongly favors ds-enolate 9, because the dominant unfavorable A) 3 interaction in the disfavored transition structure 2 is pronounced for R = NEt2. The effect sufficiently dominates to the extent that the addition of HMPA does not alter the cis/trans ratio 

There are numerous examples of diastereoselective alkylations of chiral enolates, in which the extant asymmetry of the substrate exerts suitable stereochemical control in the alkylation step [15, 20]. Several useful guiding principles have been determined to aid in predicting the stereochemical outcome. The examples discussed in the following sections have been selected to showcase the power of enolate alkylations for the stereoselective formation of new C-C bonds, as well as to highlight selected historical aspects in the development of the field. 

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Enantioselective -Functionalization of Aldehydes and Ketones The direct and enantiosective functionalization of enolates or enolate equivalents with carbon-, nitrogen-, oxygen-, sulfur- or halogen-centered electrophiles represents a powerful transformation of chemical synthesis and of fundamental importance to modem practitioners of asymmetric molecule constmction. Independent studies from List, J0rgensen, Cordova, Hayashi, and MacMiUan have demonstrated the power of enamine catalysis, developing catalytic enantioselective reactions such as... 

Section 12.2 closes with the a-functionalization of enols with C electrophiles (Figure 12.11-12.15). Figure 12.11 presents a tert-butylation of malonic ester with tert-butyl chlo-... 

Stereoselective functionalization of enolates derived from 2-acyl-2-alkyl-1,3-dithiane 1-oxides Stereoselective enolate alkylation. There has been much interest over recent years in the enantio- and diastereocontrol of enolate alkylation.19 Most methods which do not rely on asymmetric alkylating agents hinge on a derivatization of the ketonic substrate with an enantiomerically pure auxiliary. Examples of such chiral auxiliaries include oxazolines20 and oxazolidi-nones.21 We reasoned that the sulfoxide unit present in our 2-acyl-2-alkyl-1,3-dithiane 1-oxide substrates might be expected to influence the transition-state geometry of a ketone enolate, perhaps by chelation to a metal counterion, and hence control the stereochemistry of alkylation. 

Figure 5. Stereoselection in cyclopropane formation as a function of enolate stereochemistry...

Enantioselective functionalization of enolates - protonation, alkylation, arylation,... 

Transition-state analysis has been reported for acid-catalysed hydrolysis of the enol ether functionality of enol pyruvylshikimate 3-phosphate for which rate-determining C(3) protonation precedes attack of H2O 2- " C, 3- " C, 3,3- H2, and solvent deuterium KIEs have been discussed." " ... 

Enolate geometry is a structural parameter that needs to be effectively controlled in order to achieve stereoselective a-functionalization of enolates [15]. Pioneering studies by Ireland elegantly addressed this aspect and generated methods for the stereocontrolled preparation of ester enolates (Scheme 3.1) [36]. The preferential formation of the trans-ester enolate 6 under conditions of kinetic control (LDA, THF) is suggested to proceed through transition... 

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