Homoenolates homoaldol’ reaction

Stereoselectivity in the homoaldol reaction Introduction Homoenolisation and homoenolates... 

Perhaps the only true homoenolates used in synthesis are derived by metallation of derivatives of 3-haloacids. The acids themselves 12 give lithium 3-halocarboxylates 13 and hence by metallation the homoenolate which probably exists as 15, an analogue of the dilithium enolates of carboxylic acids (chapter 2). Reaction 16 with aldehydes or ketones gives y-lactones 19, by a homoaldol reaction via y-hydroxyacids 18, common products from addition of acid homoenolates to carbonyl compounds.3... 

Corey s method20 relies on metal exchange with the bromocyclopropane 69 prepared by carbene addition. The extra stabilisation of cyclopropyl anions (chapter 8) makes both this lithium derivative and the ylid 63 more easily handled. Addition to aldehydes or ketones gives mixtures of adducts 70 [it turns out that none of the stereochemistry of 69 or 70 matters] which fragment under Lewis acid catalysis to give the thioacetal 71. Careful hydrolysis releases the 3,4-enal -72, the product of a homoaldol reaction with an aldehyde homoenolate and RCHO and a difficult compound to make as the double bond moves into conjugation very easily. 

The most sophisticated homoenolate equivalents, and the first to allow some control over stereochemistry, are the lithium derivatives 160 of allyl carbamates 159 introduced by Hoppe.1 They are particularly valuable for reaction with an aldehyde or a ketone in a homoaldol reaction. 

Addition of a homoenolate to a carbonyl compound, which may be called a homoaldol reaction , provides a straightforward route to 4-hydroxy esters and y-lactones. Only two classes of well-characterized homoenolates that undergo nucleophilic addition to carbonyl compounds are known, namely titanium and zinc homoenolates of esters. 

The Merck labs described a process for conpling an asymmetric homologation to an asymmetfic homoaldol reaction in a previous communication. In this tandem asymmetric transformation, chiral amide enolates derived from aminoindanol amides (I) were homologated to the zinc homoenolates... 

Several other chiral homoenolate anion equivalents have been successfully exploited for asymmetric homoaldol reactions, e.g. (48) and (49), ° but their preparation seems more laborious than that of the carbamates (47). 

Hoppe has extended this work to d3 reagents 159 (homoenolates - see chapter 13 for achiral versions) by the addition of a double bond.29 Lithiation occurs at C-l by removal of one of the enantiotopic protons at C-3. Aldol reaction with acetone occurs at C-3 of the complex 160 as expected for a homoenolate (chapter 13) giving a single enantiomer of the homoaldol product 161. All these reactions use an excess of sparteine. 

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