Homoenolates synthesis

Stereoselectivity of chiral homoenolate equivalents in synthesis of heterocycles 99S365. 

NHC-catalysed homoenolate generation has been applied by Bode and Struble in the formal synthesis of the natural product salinosporamide A [77], The key step in the synthesis is a late-stage NHC-catalysed intramolecular lactonisation step of intermediate 186. When this reaction was attempted with an achiral triazolium-derived NHC, a 4 1 diastereomeric ratio of products was obtained in preference for the undesired product 189. In order to circumvent this, chiral triazolium salt 187 was employed, giving an approximately 1 1 mixture of desired undesired diastereoisomers (Scheme 12.41). 

Scheme 12.41 Homoenolate methodology in natural product synthesis...

As discussed in Section 12.2.2, homoenolates can be accessed from a-hydroxy-enones, and an asymmetric synthesis of cyclopentenes has been achieved using this strategy with enones (Scheme 12.42) [15]. 

The addition of a titanium homoenolate 115 to a proline derivative 114 proved to be a feasible approach for the formal synthesis of pumiliotoxin 251D. The addition proceeded with high stereoselectivity (Scheme 30) <1999JOC1410>. 

The homoenolate conjugate addition has been used very recently by Paquette and Cheney [17] to synthesise the key diquinane intermediate 18 in their studies directed towards the total synthesis of trixikingolide (Scheme 5.13). 

From the point of view of the synthesis of dissonant systems the most important finding reported by Reissig [19c] is the opening of cyclopropanes by fluoride ion-induced desilylation to give carboxylic ester stabilised "homoenolate" anions, from which a series of 4-oxoalkanoic esters (21a ). with a 1,4-D relationship, were prepared (Table 5.6) ... 

TABLE 5.6. Synthesis of 4-oxoalkanoic esters 21a via homoenolate (with NEtj. 2HF)... 

Vicinally donor-acceptor-substituted cyclopropanol carboxylic esters have been proven to be versatile synthetic building blocks in organic synthesis [11]. They readily undergo a retroaldol reaction, thus creating a stable enolate that at the same time can be considered as a homoenolate in relation to the newly formed carbonyl function. Shimada et al. applied this strategy to the preparation of y-substituted lactones starting from cyclopropane 21 (Scheme 3) [12]. 

The application of mixed enolates/homoenolates of type 14 for the racemic synthesis of y-butyrolactones has been already discussed (cf. Scheme 1). An ingenious way to render this strategy asymmetric was demonstrated with the regio- and stereoselective carbolithiation of 114, generating the organolithium intermediate 115, which could be reacted with the appro-... 

Homoenolates generated catalytically with NHCs can also be employed for C-C and C-N bond formation. Bode and Glorias have independently accomplished the diastereoselective synthesis of y-butyrolactones by annulation of enals and aldehydes [121, 122]. Bode and co-workers envisioned that increasing the steric bulk of the acyl anion equivalent would allow reactivity at the homoenolate position. While trying to suppress the competing benzoin and enal dimerization the authors comment on the steric importance of the catalyst. Thiazolium pre-catalyst 173 proved unsuccessful at inducing annulation. A-mesityl substituted imidazolium salt 200 was found to provide up to 87% yield and moderate diastereoselectivities (Scheme 34). 

Concurrently, Glorius and co-workers reported the synthesis of y-butyrolactones under similar reaction conditions [122, 123], Glorius has extended this reactivity to include trifluoromethyl ketones (Scheme 36). In addition to intermolecular reactions, intramolecular homoenolate additions are possible in modest yield Eq. 21 [123],... 

Nair and co-workers reported the diastereoselective synthesis of spiro y-butyro-lactones from 1,2-dicarbonyls [125]. The authors studied the reaction with 1,2-cyclohexane dione 230 which produces the desired lactone 232 in good yields Eq. 22a. Isatins 233 are more reactive, but the products 235 are obtained as a 1 1 separable mixture of diastereomers Eq. 22b. The Nair research group extended this methodology to include homoenolate addition to tropanone 236 to form bicyclic 5-lactones 238 Eq. 22c [126]. 

If the mesomeric stabilization is provided by a double bond, the lithiated species is a homoenolate synthon, as shown in Scheme 44a. Reaction with an electrophile typically occurs at the y-position, yielding an enamine, which can then be hydrolyzed to a carbonyl compound. An important application of this approach is to incorporate a chiral auxiliary into the nitrogen substituents so as to effect an asymmetric synthesis. 2-AzaaUyl anions (Scheme 44b), which are generated by tin-lithium exchange, can be useful reagents for inter- and intramolecular cycloaddition reactions. ... 

Nonetheless, homoenolates have been much talked about as a species useful for carbon-carbon chain extension, and a number of "homoenolate equivalents have been prepared and used for organic synthesis. Reviews on these species have been published [6]. 

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. 

Among isolable metal homoenolates only zinc homoenolates cyclize to cyclo-propanes under suitable conditions. Whereas acylation of zinc alkyls makes a straightforward ketone synthesis [32], that of a zinc homoenolate is more complex. Treatment of a purified zinc homoenolate in CDC13 with acid chloride at room temperature gives O-acylation product, instead of the expected 4-keto ester, as the single product (Eq. (22) [33]). The reaction probably proceeds by initial electrophilic attack of acyl cation on the carbonyl oxygen. A C-acylation leading to a 4-keto ester can, however, be accomplished in a polar solvent Eq. (44)-... 

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). 

The synthesis started with the homo-Reformatsky reaction between the alkoxytitanium homoenolate Eq. (30) and aldehyde 27, which afforded the product 28 with Cram orientation with >6 1 selectivity. An inversion at the sterically hindered C22 position was readily achieved by mesylation, followed by KOH treatment in hot aqueous MeOH to give lactone 30 after add-catalyzed lactonization. 

Scheme 8 Synthesis of 1-Hydroxyethylene Peptides by Addition of a Titanium Homoenolate to an a-Amino Aldehyde4 7 ...

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