Homoenolate chemistry

DePuy, as early as 1966 [14], reported that cw-1-methyl-2-phenylcyclopropanol gave exclusively deuterated 4-phenyl-2-butenone in 0.1 M NaOD/D20/dioxane. However, homoenolates derived from simple cyclopropanols by base-induced proton abstraction fail to react with electrophiles such as aldehydes and ketones, which would afford directly 1,4-D systems. Lack of a reasonably general preparative method was another factor which impeded the studies of homoenolate chemistry. For this reason, in the past twenty years more elaborated cyclopropanols, which might be suitable precursors of "homoenolates", have been prepared and studied. 

The chemistry of cyclopropanol [7] has long been studied in the context of electrophilic reactions, and these investigations have resulted in the preparation of some 3-mercurio ketones. As such mercury compounds are quite unreactive, they have failed to attract great interest in homoenolate chemistry. Only recent studies to exploit siloxycyclopropanes as precursors to homoenolates have led to the use of 3-mercurio ketones for the transition metal-catalyzed formation of new carbon-carbon bonds [8] (vide infra). 

The recent surge of interests in metal homoenolate chemistry has been stimulated by the recognition that the siloxycyclopropane route can afford novel reactive homoenolate species that are stable enough for isolation, purification, and characterization. The stability of such homoenolates crucially depends on the subtle balance of nucleophilic and electrophilic reactivity of the two reactive sites in the molecule. Naturally, homoenolates with metal-carbon bonds that are too stable do not serve as nucleophiles in organic synthesis. 

The fact that the above reactions allow isolation of 4-hydroxyesters, which are often unstable and lactonize quickly, is a merit of the homoenolate chemistry. Mesylation of the hydroxy group followed by appropriate operations provides stereocontrolled routes to y-lactones and cyclopropane carboxylates [19]. Through application of such methodology steroid total synthesis has been achieved (Section 7). 

As demonstrated in the preceding chapters, metal homoenolate chemistry centered around the ring cleavage of siloxycyclopropanes has realized a number of straightfoward synthetic transformations only some of which habe been possible with other existing methods. 

The current state of metal homoenolate chemistry is still in its infancy, and very few examples of the actual applications have been reported. However, the diversity of reactivities of the homoenolates shown in the preceding paragraphs will definitely lead future activities towards fruitful applications. 

Cyclopropanone itself is a very unstable compound that has been isolated only at low temperature. Its chemistry has been studied thoroughly during the past several years.6 Various forms of homoenolates have also been investigated, and their applications in synthesis are being actively developed.7 The combination of cyclopropanone and homoenolate chemistry employed here is most closely related to studies of Narasimhan8 and follows from a series of studies in the laboratory of the... 

Nitriles and esters are also unreactive in Smh-promoted Barbier reactions. A very useful procedure for lactone synthesis has been developed making use of this fact. Treatment of 7-bromobutyrates or 8-bro-movalerates with Smh in THF/HMPA in the presence of aldehydes or ketones results in generation of lactones through a Barbier-type process (equations 25 and 26). This nicely complements the -metaUo ester or homoenolate chemistry of organosamarium(III) reagents described above (Section 1.9.2.1), and also the Reformatsky-type chemistry promoted by Sml2 (Section 1.9.2.3.2). Further, it provides perhaps the most convenient route to 7- and 8-carbanionic ester equivalents yet devised. 

This chapter describes the chemistry of carbanionic species having a carbonyl function at the -posi-tion, relative newcomers among synthetically useful carbanionic species. The chemistry of homoenolates is complicated by the problem of tautomerism between oxyanionic and carbanionic isomers through a process that formally involves homoconjugation. The synthetic problem caused by this tautomerism is much more severe in homoenolate chemistry (Scheme 1) than in enolate chemistry (Scheme 2), which also has a similar problem, since the carbanionic tautomer (1 Scheme 1) once formed often undergoes rapid and irreversible cyclization to the oxyanionic tautomer (2), and rarely acts as a carbon nucleophile. Until recently, therefore, chemists have not been able to make use of carbanionic homoenolates for organic syntheses. " However, a large number of useful homoenolate reactions have recently been discovered, and are described in this chapter. 

In 2008, the Scheldt group reported a direct electrophilic amination via homoenolates catalyzed by N-heterocyclic carbenes using l-acyl-2-aryldiazenes as the electrophilic acceptors, which further increased the versatility of the homoenolate chemistry. It is worthwhile to note that only electron-rich substituents on the aryl component of the diazene could result in product formation (up to 84% yield), while electron-poor aryl substituents gave a lowyield (25%). An example of an asymmetric version of this new ami-nation reaction was achieved with the utilization of the chiral triazolium salt developed in their own group, providing the pyrazolidinone product in good yield (61%) and excellent enantioselectivity (90% ee) (Scheme 7.51). 

The reaction of 2/f-chromene-3-carboxaldehyde (168, R = H) with p-fluoro-benzaldehyde in the presence of an NHC and base was expected to produce a lactone, via homoenolate chemistry of (168). Instead, 3-methyl-2//-chromene-2-one (169, R = H, i.e. 3-methylcoumarin) was formed. The unexpected result was obtained again with the benzaldehyde omitted. Using a 2-methyl substrate (168, R = Me) results in a similar product, that is, 3-et/iy/coumarin (169, R=Me). ... 

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