2-Cyclohexenone, 4,4-disubstituted

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). 

Irradiation of 4,4-dialkyl-2-cyclohexenones affords bicyclo[3.1. OJhexanones in a so called lumiketone rearrangement (3.22) 337). The reaction proceeds with inversion of configuration on the disubstituted C-atom (3.23) 338). 

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. 

The first asymmetric procedure consists of the addition of R2Zn to a mixture of aldehyde and enone in the presence of the chiral copper catalyst (Scheme 7.14) [38, 52]. For instance, the tandem addition of Me2Zn and propanal to 2-cyclohexenone in the presence of 1.2 mol% chiral catalyst (S, R, R)-1S gave, after oxidation of the alcohol 51, the diketone 52 in 81% yield and with an ee of 97%. The formation of erythro and threo isomers is due to poor stereocontrol in the aldol step. A variety of trans-2,3-disubstituted cyclohexanones are obtained in this regioselective and enantioselective three-component organozinc reagent coupling. 

A structural requirement for the asymmetric Birch reduction-alkylation is that a substituent must be present at C(2) of the benzoyl moiety to desymmetrize the developing cyclohexa-1,4-diene ring (Scheme 4). However, for certain synthetic applications, it would be desirable to utilize benzoic acid itself. The chemistry of chiral benzamide 12 (X = SiMes) was investigated to provide access to non-racemic 4,4-disubstituted cyclohex-2-en-l-ones 33 (Scheme 8). 9 Alkylation of the enolate obtained from the Birch reduction of 12 (X = SiMes) gave cyclohexa-1,4-dienes 32a-d with diastereoselectivities greater than 100 1 These dienes were efficiently converted in three steps to the chiral cyclohexenones 33a-d. 

In early 1994, Padwa et al. (119) synthesized both mono- and bicyclic core skeletons of the illudins and ptaqualosins. By utilizing a 1,1-disubstituted cyclopropane as the core of the dipolar cycloaddition, Padwa was able to add a number of dipolarophiles including cyclopentenone and cyclohexenone to produce cycloadduct 233 amenable to subsequent transformations to form the illudins and ptaqualosins. The cycloaddition forms the bicyclic constrained ether in... 

Intramolecular nitrile oxide-alkene cycloadditions also provide efficient access to six-membered rings such as cyclohexanes or decalins that are heavily adorned with functional groups and side chains. For example, this strategy was used to prepare racemic hemaldulcin (213), which is a 3,6-disubstituted cyclohexenone found in a Mexican plant that possesses a strong sweet taste. Starting from (2Z,6E)-famesal (209) (328) (Scheme 6.88), the aldehyde was treated with hydroxylamine... 

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... 

Chiral 4,4-disubstituted cyclohexenones.1 The chiral bicyclic lactam 2, obtained by reaction of 4-acetylbutanoic acid with 1, on dialkylation gives mainly the diastereomer from endo-attack, with the highest diastereoselectivity obtained by using the larger electrophile in the second alkylation. Hydride reduction followed by hydrolysis furnished 4,4-dialkylated cyclohexenones (4) in >95% ee. 

The addition of carbon nucleophiles to complex (27), followed by demetallation, is equivalent to the y-alkylation of cyclohexenone. This overall transformation can also be accomplished directly via addition of electrophiles to dienolsilanes, but it becomes nontrivial for cases where the cyclohexenone C-4 position is already substituted.37 On the other hand, 1 -substituted cyclohexadienyliron complexes, such as (30), react very cleanly with certain carbon nucleophiles, at the substituted dienyl terminus. This provides useful methodology for the construction of 4,4-disubstituted cyclohexenones, and has been employed in a variety of natural product syntheses. 

Monocyclic phenols and their methyl ethers react with benzene in HF—SbF5 medium to provide 4,4-disubstituted cyclohexenones 237 [Eq. (5.308)].3O1para-Methylanisole gives three products two cyclohexenone derivatives [see Eq. (5.112)] and an interesting tricyclic ketone 238. 

The reaction of 2,2-disubstituted 1,3-cyclohexanediones 1 with dimethyl methanephosphonate in THF in the presence of LDA gives 3-substituted 2-cyclohexenones 2 in moderate to very good yields. 

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. 

XXXVIII) is obtained from cyclohexanone (n = 1) the product is primarily the cis isomer. A mixture of the cis and trans products is obtained from cyclohep-tanone (n = 2), whereas from the cyclooctanone (n = 3) the product is primarily the trans isomer (XXXIX). Similar effects are also observed in the hydrogenation of the bicyclic systems (XL) in acidic media, as shown in Table V (50). The hydrogenation of 3,5-disubstituted cyclohexenones (XLI) gives exclusively cis-disubstituted cyclohexanones regardless of reaction conditions (22). 

Cyclohexadiene-Fe(CO)i complexes. Pearson has reviewed the formation and reactions of these complexes. One particularly inteiesting property is the ability of a methoxy group to direct attack of nucleophiles to the / disubstituted cyclohexenones (3), including spirocyclic compounds. 

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). 

Despite the obvious advantages the catalytic methods suffer from some limitations. A considerably lesser degree of regioselectivity was observed in the oxyamination reactions of terminal alkenes and asymmetrically disubstituted alkenes, such as 1-phenyl-1-propenes, with respect to the comparable results from stoichiometric reactions (cf. Tabic 5 and 6). Furthermore, reduced reactivity was observed, In fact, neither method (A or B) was successful with tetramethylethylene, cholesteryl acetate, diethyl ( )-2-butenedioate, 2-cyclohexenone, 1-acetoxycyclohexene or 1-phenylcyclohexene73. 

Table 5) [28], and heteroatom Diels-Alder reactions (Sch. 50) [79,80] but no X-ray structure had ever been reported for it or for the 3,3 -disubstituted derivatives which were first introduced as an asymmetric Claisen catalyst [24-27]. Although compound 435 was found not to induce any reaction between cyclohexenone and phosphonate 425 under the standard conditions for catalyst 428, consistent with the proposed equilibrium of species 394, 431, 432, 433, and 434 is the finding that catalysis of the reactions between cyclohexenone or cyclopentenone and phosphonate 425 with a 2 1 mixture of 434 (M = Li) and 435 gave only the Michael adducts 426 and 427 in 96 % ee and 92 % ee, respectively. Because 394 and 432 are inactive catalysts and 434 results in much lower induction and some 1,2-adduct, it was proposed that the active catalyst in the Michael addition of phosphonate 425 to cyclohexenone was the species 431 resulting from association of ALB catalyst with a metal alkoxide. It was proposed that the stereochemical determining step involved intramolecular transfer of the enolate of 425 to the coordinated cyclohexenone in species 436. 

Wittig methodology has been used to prepare a variety of heterocyclic species, including cyclopentenones and cyclohexenones through the intramolecular Wittig reaction of 2-oxoalkylidenetriphenylphosphoranes (52) (Scheme 14), fluor-inated butanolides and butenolides, 2,5-disubstituted-pyrroles and -pyr-rolidenes, which utilised the phosphorane 4-[ 4-methylphenyl)sulfonyl]-l-... 

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