Tandem conjugate addition-enol trapping

A synthesis of this compound was devised by Ohmizu, Iwasaki and co-workers and featured a three-component tandem conjugate addition/enolate trapping as key step (Scheme 12.24) [82]. In this synthesis, the acyl anion equivalent cyanohydrin 165 was first treated with LDA and allowed to react with methyl crotonate 166. The resulting enolate was trapped with 2,3,5-trimethoxy benzylbromide 168 to afford crude intermediate 169, which was immediately deprotected in situ to afford ketone product 170. Both the ester and the ketone functionalities were then reduced at low temperature to afford the corresponding diol 171. Upon treatment with trifluoroacetic acid, the desired Friedel-Craft cyclization adduct 172 was obtained. The latter tricyclic compound was then further elaborated to the final target 164 through a short sequence of standard transformations. 

The reaction has been further extended into a tandem conjugate addition/ enolate trapping sequence, whereby the in situ generated zinc enolate was trapped with benzaldehyde. This resulted in an approximately 3 7 mixture of trans-erythro trans-threo aldol adducts, isolated in 88% yield. Subsequent oxidation of these products gave a single isomer of the corresponding diketone with 95% ee. 

Feringa and co-workers reported a new enantioselective Cu(I)/Tol-BINAP-cata-lyzed tandem conjugate addition-enolate trapping reaction of Grignard reagents with 4-chloro-a,p-unsaturated esters, thioesters, and ketones to yield tran -l-alkyl-2-substituted cyclopropanes in up to 92% yield and up to 98% ee (Scheme 38)... 

Various groups have reported that additions of a-hetero substituted ester enolates to a,3-enones are temperature dependent, l40 c but, in general, the 1,2 to 1,4-equilibration of a-seleno and a-thio substituted ester adducts occurs at lower temperature than the a-oxo substituted ester adducts. In contrast to the simple ester enolates, the a-hetero substituted ester enolates are extremely useful for functionalization of alicyclic a,(3-enones with the tandem conjugate addition-electrophile trapping protocol, as shown... 

The general reaction sequence has been named more specifically as tandem vicinal dialkylation, nucleophilic-electrophilic carbacondensation,11 dicarbacondensation1213 or conjugate addition-enolate trapping,14 usually in reference to the fact that most of the reaction examples available create two new vicinal carbon-carbon bonds. Many noncarbon nucleophiles and electrophiles also are known, resulting... 

Several attempts to take advantage of the intermediate boron enolate to achieve tandem conjugate addition-aldol reaction have been proposed [71]. Recently, Chandrasekhar [72] reported the addition of triethylborane to methyl vinyl ketone followed by the in situ trapping of the enolate by aromatic aldehyde (Scheme 26). 

Welch s stereoselective synthesis centered about the tandem conjugate addition of a methyl group and allylation to produce 583 (Scheme XLVI). A second methylation, combined with oxidation of the allyl sidechain, gave 584 which was successfully cyclized under Claisen conditions. Trapping of the enolate as in 585 permitted differentitation between the two potential ketone carbonyl groups. 

To extend the scope of the carbometallative aldol cycloreduction, the feasibility of Cu-catalyzed conjugate addition-aldol cyclization process was examined. Cu-catalyzed addition of organozinc compounds to o ,jS-unsaturated carbonyl compounds has been well established (169-171,187-189). Trapping of the Zn-enolates using aldehydes (169,188,190) and acetals/ketals (191) has been reported however, the use of ketones as electrophiles to trap Zn-enolates failed in the absence of strong Lewis acids (191). Rrische and co-workers reported the first successful example of Cu-catalyzed tandem conjugate addition-aldol cyclization with ketones, esters, and nitriles as electrophiles (Scheme 107) (192). In this cyclization process, enone-ketones 237 and 239 afforded products in good to excellent... 

Scheme 38 Asymmetric tandem conjugate addition-intramolecular enolate trapping reaction...

Several examples of conjugate addition of carbanions carried out under aprotic conditions are given in Scheme 2.24. The reactions are typically quenched by addition of a proton source to neutralize the enolate. It is also possible to trap the adduct by silylation or, as we will see in Section 2.6.2, to carry out a tandem alkylation. Lithium enolates preformed by reaction with LDA in THF react with enones to give 1,4-diketones (Entries 1 and 2). Entries 3 and 4 involve addition of ester enolates to enones. The reaction in Entry 3 gives the 1,2-addition product at —78°C but isomerizes to the 1,4-product at 25° C. Esters of 1,5-dicarboxylic acids are obtained by addition of ester enolates to a,(3-unsaturated esters (Entry 5). Entries 6 to 8 show cases of... 

A tandem aldol condensation-radical cyclization sequence has been developed for the preparation of functionalized bicyclo[3.3.0]octane systems [116]. Conjugate addition of Me2AlSePh to dimethylcyclopentanone (118) followed by trapping of the resulting enolate with aldehyde gave predominantly the trans, erythro aldol 119 this then underwent radical cyclization with BusSnH and catalytic AIBN yielding the bicyclic ketol 120 stereospecifically (Sch. 80). 

The conjugate addition of a nucleophile to a, 3-unsaturated carbonyl compounds results in formation of the corresponding enolate subsequent to the initial addition step. This reactive intermediate can be trapped by a variety of electrophiles, and thus opens up opportunities for tandem reaction sequences [108]. 

Scheme 8.3. Tandem Reactions Involving Trapping of Enolates Generated by Conjugate Addition...

Tandem reactions involving trapping of enolates generated by conjugate addition of organocopper reagents... 

A powerful tandem 1,4-addition/cyclization was reported by Danishefsky in the total synthesis of avermectin A,., (15, Scheme 12.2) [53-55]. In the sequence, conjugate addition of thiophenoxide to enal 12 generates an intermediate enolate that is trapped by addition to the resident ketone. Subsequent oxidation of the sulfide in 13 to the corresponding sulfoxide and thermolysis provided the desired oxahydrindene 14 in 76% overall yield [54]. From advanced intermediate 14, only a few steps were required to complete the synthesis of the anthelmintic agent avermectin Aj (15) [54, 55], Fukumoto developed a stereoselective double Michael sequence for the construction of substituted bicyclo[2.2.2]octanes (Scheme 12.3) [56, 57]. The intramolecular transformation was conducted by treatment of 16 with base and afforded 17 as a single isomer in 58% yield. The sequence is no-... 

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