1,4-addition acyclic enones

The poor diasteroselectivity at the yS-carbon of cyclic enones arises from poor facial selectivity during cuprate addition. Acyclic enones may also give poor dia-stereoselectivity at the y8-carbon center because of E Z isomerization arising from an equilibrium between an enone-cuprate d-re complex and starting materials. Much work remains to be done in the development of asymmetric variations in a-aminoalkylcuprate chemistry. 

Organoboron reagents ate pariictdarly well suited for 1,4-additions of aryl and vinyl groups to enones. Hayasbi et al. developed a highly enantioselective RliQ)/ BlNAP-catalyzed 1,4-addilion of pbenylbotonic add lo cyclic and acyclic enones [24] fSclieme 7.5) and 1-alkenylpbospbonales [25]. 

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...

Another chiral cuprate that shows high diastereoselectivity on addition to cycloalkcnones is the dihydropyrazine derivative 12. The adducts 13 were obtained in good chemical yield with diastereoselectivities exceeding 90% A Lower diastereoselectivities resulted on addition of 12 to /(-substituted cycloalkenones or to acyclic ( )-enones. 

The stereochemical outcome of these reactions has been rationalized as arising from a "tram-de-calyl -like or trans-fused chair-chair -like transition state. The extension of these reactions to acyclic enones has not been successful and only y-1,2-addition products are formed153. 

Addition of lithiated Ar-(4-methylphenylsulfonyl)-S-phenyl-S -(2-propenyl)sulfoximine to acyclic enones gives exclusively 1,4-a-adducts in high diastereomeric purity. The configuration of the adduct (R2 = R3 = C6H5) has been determined by a single crystal X-ray structure determination27. 

Kinetically controlled 1,4-additions of 2-propenylsilanes to acyclic enones bearing a benzyloxy group in the 4-position proceeded with moderate stereoselectivity using titanium(IV) chloride as the preferred Lewis acid. The stereochemical outcome was dependent on the geometry of the enone used26. 

The optimal reaction conditions were applied with 59d in the addition of various aryl boronic acids and potassium trifluoroborates to several cyclic and acyclic enones (Fig. 8). Arylboronic acids added to cyclic enones in high yields (89-97%) and with good to excellent selectivities (85-98% ee). Under these conditions, the potassium trifluoroborate reagents reacted at faster rates, but with slightly lower selectivities (83-96% ee). The reactions of acyclic enones with aryl boron reagents gave also excellent yields (83-96%). 

An arenethiolatocopper (I) complex has been used by van Koten et al. to catalyse the 1,4-Michael addition of Grignard reagents to acyclic enones, providing the corresponding products with excellent chemoselectivities, high... 

Scheme 2.18 Cu-catalysed 1,4-additions of RMgl to acyclic enones with arenethio-latocopper (I) complex.

In order to prepare a new range of ligands incorporating both sulfoximine and phosphine moieties, Tye et al. reported, in 2001, the synthesis of a novel chiral phosphine-sulfoximine, which was tested as a ligand in the copper-catalysed 1,4-addition of ZnEt2 to enones. Whilst the reaction of acyclic enones gave the corresponding racemic 1,4-products, the best result was obtained upon... 

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. 

Aryl-substituted enones such as chalcone and benzalacetone have been used as model substrates in the study of asymmetric 1,4-addition of acyclic enones. Many chiral ligands have been found to afford good enantioselectivities (Scheme 19). Typical results are summarized in Table i 46>50 58-66... 

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... 

Woodward and co-workers utilized [Gu(MeCN)4]BF4 and (A)-BINOL-derived thiourethane ligand 87 in the addition reaction of trimethylaluminum to acyclic enones. Both yields and enantioselectivities were moderate (Scheme 44).130... 

The use of copper catalysts based on chiral phosphorus ligands to assist 1,4-additions of dialkylzinc reagents has in recent years produced major breakthroughs, with excellent enantioselectivities. A number of monodentate and bidentate phos-phoramidites, phosphites, phosphonites, and phosphines are now available as chiral ligands for alkyl transfer to a variety of cyclic and acyclic enones. So far. 

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