2-Cyclohexenone, 4,4-disubstituted synthesis

The synthesis of this series involved the reaction of disubstituted or benzo fused 6-keto(formyl)-2-cyclohexenones with hydroxylamine (Scheme 176), Base degradation gave a-cyanoketones which can be further degraded to diacids (67AHC(8)277, 80IJC(B)406). 

Tandem 1,4-addition to cycloalkenones constitutes an extremely versatile and elegant methodology for the synthesis of 2,3-disubstituted cycloalkanones, as is evident from its application in areas such as prostaglandin synthesis. Noyori et al. have reported the use of organozinc reagents in copper-catalyzed tandem additions [64]. The zinc enolate resulting from the catalytic enantioselective 1,4-addition of Et2Zn to cyclohexenone reacts readily with an aldehyde in a subsequent aldol condensation. 

In the asymmetric synthesis of 4,4-disubstituted cyclohexenones of the type (132) it was possible to raise the optical yield to a maximum of 54 % by varying the structures of the carbonyl compounds 150) and of the proline derivatives (131)151). 

This reaction has been extended to an enantioselective synthesis of 4,4- and 6,6-disubstituted cyclohexenones (equation 111). Thus (2S,3S)-2, prepared by the above procedure, is converted in two steps to the 1,5-diketone 3. The aldol ring closure of 3 results in either 4 or 5, depending on the conditions each product is obtained in 86% oplical yield.4... 

A general methodology for the construction of quaternary carbon atoms at the carbonyl carbon of ketones has been successfully exploited for the facile synthesis of ( )-lycoramine (299) (Scheme 30) (165). Thus, the O-allylated o-vanillin 322 was allowed to react with vinyl magnesium bromide followed by Jones oxidation, and the acid-catalyzed addition of benzyl IV-methylcarbamate to the intermediate a,(3-unsaturated ketone furnished 323. Wadsworth-Emmons olefination of 323 with the anion derived from diethyl[(benzylideneami-no)methyl]phosphonate (BAMP) provided the 2-azadiene 324. The subsequent regioselective addition of n-butyllithium to 324 delivered a metalloenamine that suffered alkylation with 2-(2-bromoethyl)-2-methyl-l,3-dioxolane to give, after acid-catalyzed hydrolysis of the imine and ketal moieties, the 8-keto aldehyde 325. Base-catalyzed cycloaldolization and dehydration of 325 then provided the 4,4-disubstituted cyclohexenone 326. The entire sequence of reactions involved in the conversion of 323 to 326 proceeded in very good overall yield and in one pot. 

A 4,4-disubstituted cyclohexenone synthesis has been developed by Holmes and Madge. The procedure is based upon PAA oxidation of anisole-derived bicyclo[2.2.2]oct-S-en-2-ones, followed by acid-catalyzed isomerization of the products (Scheme 21). 

Meyers and his group have published an interesting asymmetric synthesis of chiral 4,4-disubstituted cyclohexenones which depends on the sequential alkylation of the chiral aldehydo-ketone equivalent (18). Because alkylation occurs preferentially from the less hindered, lower face, both enantiomers are available from this... 

A multistep conversion of 2,2-disubstituted 1,3-cyclohexadiones 191 to 3-substi-tuted 2-cyclohexenones 192 mediated by phosphonate anions was applied by Yamamoto and Furuta [69] in a formal synthesis of ( )-a-acoradiene (193) (Scheme 47). 3-Substituted 2-cyclohexenones are versatile building blocks for the synthesis of cyclic natural products such as spirocyclic and fused ring sesquiterpenes. These cyclohexenones were easily obtained in a one-pot reaction of 194 with dimethyl methanephosphonate anion in the presence of trimethylsilyl chloride. The new overall reaction is a multistep rearrangement involving... 

In 1969 Yamada and Otani reported an stereoselective stoichiometric synthesis of 4,4-disubstituted 2-cyclohexenones through an asymmetric Robinson annula-tion between preformed chiral aldehyde L-proline-derived enamines 20 and methyl vinyl ketone (Scheme 2.12) [33]. Surprisingly, only few examples of organocatalyzed Michael additions of aldehydes to enones have been reported since then. 

Based on initial studies by Krause and Alexakis [100], the highly enantioselective synthesis of trans-5-aryl-2-substituted cyclohexanones 119 was accomphshed by the conjugate arylation of racemic 6-substituted cyclohexenones 117 (Scheme 8.29) [101]. Although the first step did not proceed in a diastereoselective maimer, only the thermodynamically more stable trans-disubstituted cyclohexanone 119 was obtained after epimerization with NaOEt. 

In 2010, Carter and co-workers [47] and Kotsuki and co-workers [48] reported independently the highly enantioselective synthesis of cyclohexenones from a,a-disubstituted aldehydes and enones. In both cases, the results were excellent. In Kotsuki s paper the catalyst was a primary ammonium carboxylate, concretely... 

Strauss and Wiechers (57) have described a synthesis of ( )-0-methyl-joubertiamine (38) which is filustrated in Scheme 28. The approach used by these authors relies on use of the Claisen-Eschenmoser 3,3-sigmatropic rearrangement to create the functionalized 4,4-disubstituted cyclohexenone derivative 107. This scheme follows closely one utilized successfully by Muxfeldt and co-workers (55), reported in 1966 for the thesis of (+ crinine. The other reactions employed in the transformation of 107 to via the cyclohexenone 108 are straightforward and need no further conunent. 

Removal of the organic ligand of 47 foUowed by hydrolysis of the enol ether yields the 4,4-disubstituted cyclohexenone system and so 46 may be formally regarded as a synthetic equivalent of the cyclohexenone cation 49. This methodology has been exploited in the synthesis of a number of natural products. For example, addition of the potassium enolate 50 to cyclohexadi-enyl complex 45 resulted in formation of a neutral complex 51 containing the two contiguous quaternary centres required for the synthesis of 12,13-epoxy-14-methoxytrichothecene 52. ... 

Kinney WA, Crouse GD, Paquette LA. Regiocontrolled synthesis of monosubstituted, disubstituted, and tri-substituted cyclohexenones by cycloaddition of vinyl sulfones to l-methoxy-3-[(trimethylsilyl)oxy]-l,3-butadienes conversion of alkenes into effective dienophilic reagents. J. Org. Chem. 1983 48(25) 4986-5000. 

---