2-Cyclohexenone conjugated

The addition of large enolate synthons to cyclohexenone derivatives via Michael addition leads to equatorial substitution. If the cyclohexenone conformation is fixed, e.g. as in decalones or steroids, the addition is highly stereoselective. This is also the case with the S-addition to conjugated dienones (Y. Abe, 1956). Large substituents at C-4 of cyclic a -synthons direct incoming carbanions to the /rans-position at C-3 (A.R. Battersby, 1960). The thermodynamically most stable products are formed in these cases, because the addition of 1,3-dioxo compounds to activated double bonds is essentially reversible. 

Photochemical transformations of conjugated cyclohexenones, 317 Photochemical transformations of non-conjugatea ketones, 292 Photochemistry of cyclobutanones, 293 Photolysis of nitrites, 253... 

The first step of the Robinson annulation is simply a Michael reaction. An enamine or an enolate ion from a jS-keto ester or /3-diketone effects a conjugate addition to an a-,/3-unsaturated ketone, yielding a 1,5-diketone. But as we saw in Section 23.6,1,5-diketones undergo intramolecular aldol condensation to yield cyclohexenones when treated with base. Thus, the final product contains a six-membered ring, and an annulation has been accomplished. An example occurs during the commercial synthesis of the steroid hormone estrone (figure 23.9). 

The conjugate addition of Grignard reagents to 2-cyclohexenone was promoted by catalytic amounts (2-4 mol %) of alkylcopper(I) complexes of the lithium amide prepared from N- (R)-1 -phenylethyl]-2-[(/ )-l-phenylethyliminojcycloheptatrienamine, Li[CuR(CHIRAMT)]52,11. However, 3-substituted cyclohexanones were obtained in very low ee (4-14%). 

In contrast, a-alkoxycuprate 10, prepared from the corresponding stannane, gave the conjugate addition product with only 0-20% ee upon treatment with 2-cyclohexenone in the presence ofchlorotrimethylsilane67. However, the conjugate addition of 10 to ethyl propynoatc in the presence of chlorotrimethylsilane provided 11 in 85% yield with nearly 96% ee67. 

Conjugated cyclohexenones [6] have also been easily prepared by combining the cycloaddition of dimethylaminobutadiene 4 and several cyclic and acyclic dienophiles followed by the elimination of the amino group from the cycloadducts under acidic conditions. Scheme 2.3 summarizes some of these results. 

Roland et al. obtained 23% ee in the addition of Et2Zn to cyclohexenone using the silver(I) complex 78 having a chiral backbone and methyl groups on the nitrogen atoms. This complex acts as an efficient carbene transfer agent towards Cu(OTf)2. The conjugate addition proceeds rapidly in toluene at 0 °C (Scheme 52). 

Another class of new ligands was prepared in quantitative yields by Feringa et al., in 1997, by reaction between a-mercapto acids, aniline and 2-pyridine-carboxaldehyde." These pyridyl-substituted thiazolin-4-one ligands were further involved in the copper-catalysed conjugate addition of ZnEt2 to 2-cyclohexenone,... 

On the other hand, chiral sulfur-containing but noncoordinating ligands such as sulfonamides have been widely used in the asymmetric Michael reaction. In 1997, Sewald et al. reported the use of a series of chiral sulfonamides depicted in Scheme 2.25 in the Cu-catalysed conjugate addition of ZnEt2 to 2-cyclohexenone. Even the use of a stoichiometric amount of catalyst did not allow the enantioselectivity to be higher than 31% ee. 

Scheme 8.7. Catalytic Enantioselective Conjugate Addition to Cyclohexenone...

The only other functional group is the conjugated unsaturated ester. This functionality is remote from the stereocenters and the ketone functionality, and does not play a key role in most of the reported syntheses. Most of the syntheses use cyclic starting materials. Those in Schemes 13.4 and 13.5 lead back to a para-substituted aromatic ether. The syntheses in Schemes 13.7 and 13.8 begin with an accessible terpene intermediate. The syntheses in Schemes 13.10 and 13.11 start with cyclohexenone. Scheme 13.3 presents a retrosynthetic analysis leading to the key intermediates used for the syntheses in... 

In the synthesis shown in Scheme 13.15, racemates of both erythro- and threo-juvabione were synthesized by parallel routes. The isomeric intermediates were obtained in greater than 10 1 selectivity by choice of the E- or Z-silanes used for conjugate addition to cyclohexenone (Michael-Mukaiyama reaction). Further optimization of the stereoselectivity was achieved by the choice of the silyl substituents. The observed stereoselectivity is consistent with synclinal TSs for the addition of the crotyl silane reagents. 

Scheme 2.33. Formation of highly substituted chiral cyclohexenone derivatives using a domino conjugate addition/Dieckmann condensation.

In 1994, lithium amide 23 was used in the conjugate addition of 2-cyclohexenone to afford optically active adduct with up to 97% ee (Scheme 13).28-29 A dimeric structure was proposed as the intermediate, where the phenyl group in 23 blocked the bottom face and the cyclohexenone substrate approached from the upper face. 

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. 

Li and co-workers also reported a highly efficient conjugate addition reaction with arylsilanes as nucleophilic reagents. The reaction of 2-cyclohexenone with 4 equiv. of either diphenyldichlorosilane or phenylmethyldichlorosilane in water generated the conjugate addition product in 97% and 95% yields, respectively (Scheme 55).143 An excess of sodium fluoride additive was important in this reaction. 

Toromanoff, E., Steric Course of the Kinetic 1,2 Addition of Anions to Conjugated Cyclohexenones, 2, 157. 

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