Acyclic conjugate additions

When the cation remains coordinated to the nucleophile, the reaction is under association control. Association-controlled reactions are usually slow, because the substrate is not activated and the nucleophile is deactivated. This general class can be subdivided into two groups. In the first (which occurs in the C-alkylation of enolates), the metal is not directly bound to the reactive site. If the transition state is acyclic, conjugate additions will dominate because there is no electrophilic assistance. If it is cyclic, chelation favors addition to the carbonyl ... 

Conjugate addition reactions of acyclic Midiael acceptors possessing betetoatom-SLibstituted stereogenic centers in tlieir )>-positions may provide usefiil levels of diastereoselectivity. A typical example is given witli tlie y-alkoxy-substituted enoate 49 in Sdieme 6.8 [17]. High levels of diastereoselectivity in favor of tlie anii addition product SO were found in tlie course of dlmediylcuprate addition. 

The conjugate addition to acyclic enones is summarized in Table 5. The chiral hetero-cuprate derived from (S)-prolinol or cinchonidine produced products of low enantiomeric excess on treatment with chalcone (entries 3 and 4), while the cuprate from (S)-yV-methylpro-linol gave 64% ee (entry 6). Under more dilute conditions, 88% cc was obtained (entry 5). (2[Pg.909]

Table 5. Conjugate Addition to Acyclic Enones with External Chiral Ligands O, O...

In 2000, Gennaii et al. discovered a new family of chiral Schiff-base ligands, with the general structure, Af-alkyl-p-(A -salicylideneamino)alkanesulfonamide, depicted in Scheme 2.28. These ligands were successfully implicated in the copper-catalysed conjugate addition of ZnEt2 to cyclic enones (Scheme 2.28) and, less efficiently, to acyclic enones such as benzalacetone (50% ee) or chalcone... 

Conjugate addition to acyclic enones is subject to chelation control when TiCl4 is used as the Lewis acid. Thus, whereas the A-enone 12 gives syn product 13 via an acyclic TS, the Z-isomer 14 reacts through a chelated TS to give 15.133... 

Yamaguchi and coworkers have found that proline rubidium salts catalyze the asymmetric Michael addition of nitroalkanes to prochiral acceptors. When (25)-L-prolines are used, acyclic ( )-enones give (S)-adducts. Cyclic (Z)-enones give (R)-adducts predominantly (Eq. 4.139).203 Recently, Hanessianhas reported that L-proline (3 7% mol equiv) and 2,5-dimethylpiperazine are more effective to induce catalytic asymmetric conjugate addition of nitroalkanes to cycloal-kanones.204... 

Nickel-catalyzed conjugate addition to acyclic enones 383... 

In 1993, Alexakis et al. reported the first copper-catalyzed asymmetric conjugate addition of diethylzinc to 2-cyclohexenone using phosphorous ligand 28 (32% ee).36 An important breakthrough was achieved by Feringa et al. with chiral phosphoramidite (S,R,R)-29 (Figure 1), which showed excellent selectivity (over 98% ee) for the addition of 2-cyclohexenone.37 Since then, efficient protocols for the conversion of both cyclic and acyclic enones, as well as lactones and nitroalkenes, have been developed featuring excellent stereocontrol. 

A remarkable number of chiral phosphorus ligands (phosphoramidites, phosphites, and phosphines with modular structures) have been introduced into the copper-catalyzed conjugate addition of R2Zn reagents, and high enantio-selectivities (>90%) are now possible for all three different classes of substrates 2-cyclohexenones and larger ring enones, 2-cyclopentenones, and acyclic enones. 

Chiral binaphthylthiophosphoramide 52b and binaphthylselenophosphoramide 53 have been developed by Shi and co-workers, and high enantioselectivity (up to 97%) has been achieved in the asymmetric conjugate addition of acyclic enones under the optimized conditions.58... 

Simple acyclic a,/ -unsaturated esters are not reactive in the conjugate addition of dialkylzincs. In contrast, nitro-substituted unsaturated esters68 and malonates69 are applicable for this reaction. Using peptide-based chiral phosphine 66, Hird and Hoveyda realized the Cu-catalyzed conjugate addition of Et2Zn to iV-acyloxazolidinones with excellent enantioselectivity (Scheme 21).70... 

Feringa and co-workers applied chiral phosphoramidite ligand (S,R,R)-67 in the conjugate addition of dimethylzinc to acyclic unsaturated malonates 68 and obtained up to 98% ee (Scheme 22).71... 

The enantioselective conjugate addition of dialkylzinc to nitroalkenes using other phosphoramidite,79,79a 83a sulfonamide,84 and binaphthol-based thioether ligands65 has also been studied in the past few years. Particularly noteworthy are the efficient chiral monodentate phosphoramidite ligands (S,R,R)-29 and (A,A)-55 developed by Feringa et al. and Alexakis et al., respectively, for this reaction. (S,R,R)-29 provided excellent enantioselectivities (up to 98% ee) for acyclic nitroalkenes (Scheme 25).80 It also worked well for other nitroolefin substrates such as 3-nitrocoumarin 7068 and methyl 3-nitropropenoate 7185. 

Alexakis et al. showed that under optimized experimental conditions, the enantioselectivity of the Cu-catalyzed conjugate addition of dialkylzinc to cyclic nitroolefin was improved to 95% with both (A,A)-55 and (R,S,S)-29.79,79a Biphenol-based phosphoramidite ligand (S,S)-55 also provided acyclic nitroalkenes adducts with 95-96% ee.42... 

Ojima and co-workers found that chiral monodentate phosphoramidite (S,R,R)-35 was highly effective for the enantioselective conjugate addition of diethylzinc to acyclic nitroalkenes (up to 99% ee).86... 

Toru has investigated the stereoselectivity of the conjugate addition of trialkylboranes to 2-arylsulfinylcyclopentenones. Excellent stereocontrol is achieved with different alkyl radicals (Scheme 27) [73-76]. In the acyclic series, the lack of diastereoselectivity in the addition step and a competitive Pummerer rearrangement have limited the synthetic potential of this reaction [77]. 

Use of TMSCl in combination with HMPA, DMAP, or TMEDA all favored 1,2-addition over 1,4-addition. Sequential a-alkoxyalkylcuprate conjugate addition, enolate trapping with TMSCl, and silyl enol ether alkylation provides a one-pot synthesis of tetrahydrofurans (Scheme 3.35) [129]. Cyclic enones afford as-fused tetrahydrofurans, while acyclic systems give complex mixtures of diastereomers. a-Alkoxyalkylcopper reagents also participate in allylic substitution reactions with ammonium salts [127]. 

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