Cyclic compounds cyclohexenone

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. 

When the enol ring is adjacent to a cyclic moiety, then it is possible to achieve very short hydrogen bonds, as in the structure of usnic acid, a natural product found in lichens. A low-temperature X-ray diffraction analysis of this compound showed two enol moieties, one in which a carbon-carbon bond of the enol was part of a cyclohexenone ring, and this had... 

The aWol reactions weVe seen up to this point have all been m emolem-lar. That is, they have taken place between two different molecules. When certain dicarbonyl compounds are treated with base, however, an intraroo lecular aldoi reaction can occur, leading to the formation of a cyclic prodw For example, base treatment of a 1,4-diketone such as 2,5-hexanedion yields a cyclopentenone product, and base treatment of a 1,5-diketone sue as 2,6-heptanedione yields a cyclohexenone. 

Intermolecular de Mayo reactions are efficient for cyclic 1,3-diketones such as dimedone (5,5-dimethyl-l,3-cyclohexanedione)96,103,104 and acyclic systems such as acetylacetone93-95. Unsymmetrical acyclic /l-diketones, such as 1-phenyl-1,3-butanedione98 can enolize in two directions, however, reaction normally occurs preferentially from a single enol form. Examples of alkene photocycloaddition to trapped ends of /(-dicarbonyl compounds (e.g., 2,2-dimethyl-3(2/f)-furanone and 2,2.6-trimethyl-4/f-l,3-dioxin-4-one) are given in Table 1 (entries 26, 27) and Table 2 (entry 35) 10°. If the enol is stabilized by derivatization (e.g., acetylated dimedone 3-acetoxy-5,5-dimethyl-2-cyclohexenone), the primary cyclobutane photoproducts can be isolated96. 

Numerous studies have been conducted on the intramolecular photoaddition of cyclic enones with tethered alkenes connected at different positions of the cyclic systems. Scheme 14a summarizes the different enone systems that have been studied. Compounds 37, 38, and 39 are examples of cyclohexenone derivatives with alkene chains tethered at C-2, C-3, and C-4 positions, respec-... 

Lewis acids promote conjugate addition and the presence of a chiral ligand on the metal can result in high levels of asymmetric induction. A good example in this regard is the addition of the enolate of dicarbonyl compounds (such as dimethylmalonate) with cyclic enones (such as cyclohexenone) in the presence... 

In 2004, Hayashi and coworkers found trans-4-TBSO-(5)-proline 29 to be more active than the parent proline organocatalyst for the asymmetric a-aminojylation of enolisable aldehydes 8 (R = H) or cyclic ketones 11 (X=-CH2-, -C(Me)2-, -S-) with nitrosobenzene to prepare optically pure (>99% ee) hydrojylamine derivatives 12 or 13 in 50-76% yield (Scheme 10.2). Compound 29 (30 mol%) also efficiently catalysed the a-aminojylation/intramolecular Michael cascade reaction of cyclohexenones 34 with nitrosobenzene to afford bicyclic compounds 35 with veiy high enantioselectivity (Scheme 10.7). Furthermore, in the presence of organocatalyst 29, three-component Mannich reactions of acetone 8 (R = Me, R = H) with benzaldehyde derivatives 9 (R = Ar) and 4-metho3yaniline produced the corresponding enantiomers (90-98% ee) of p-amino ketones 16 in mild experimental conditions (—20 °C) (Scheme 10.3). 

Based on the Amaryllidaceae alkaloid galanthamine, a biomimetic solid-phase synthesis of 2527 compounds was reported by Shair and coworkers (Figure 11.13) The core scaffold, initially prepared in several steps, was diversified by means of four successive reactions Mitsunobu reaction of the phenolic moiety with five primary alcohols, Michael addition of the a, 3-unsatnrated cyclohexenone with thiols, iV-acylation or A -alkylation of the cyclic secondary amine, and treatment of the ketone with hydrazines and hydroxylamines. Further evaluation of library constituents for their ability to block protein trafficking in the secretory pathway of mammalian cells led to the discovery of sercramine as a potent inhibitor of the VSVG-GFP protein movement from the Golgi apparatus to the plasma m brane. 

The direct oxidative annulations with alkynes by Csp -H/Csp -H bond cleavage have not been developed yet only two examples were described in this area using nickel(O) by Hiyama [198] and rhodium(lll) by Wang [199]. With ruthenium (11) catalyst, Lam reported the first annulations with alkynes of 2-aryl-l,3-dicarbonyl compounds by Csp -H and Csp -H bond activation [200]. The reaction of 2-aryl-3-hydroxy-2-cyclohexenones and cyclic 2-aryl-l,3-dicarbonyl compounds with 2.5 mol% of [RuCl2(/ -cymene)]2 and 2.2 equiv. of Cu(OAc)2 was performed in 1,4-dioxane at 90°C, and led to spiroindene derivatives in 50-84%... 

As diazocarbonyl compounds bearing a substituent other than H on the diazobearing carbon, some cyclic diazoketones were applied to the Pd-mediated polymerization. The a,j3-unsaturated cyclic diazoketone 6 derived from cyclohexenone can be transformed into polymers with a unique structure, where the main chain carbon is one of carbon atoms of a six-membered ring [45] (Scheme 23). In addition, the C=C bond conjugated with C=0 would be directed outward from the main chain, which may render an attack of nucleophiles (1,4-conjugate addition) feasible. As expected, the addition of nucleophiles such as organolithium and sodium salt of diethyl malonate occurred by the reaction with the polymer. 

Enantioselective Michael addition catalyzed by chiral aluminum Lewis acid is one of the most important methods to obtain enantiomerically pure compounds. As an early work in this fleld, in 1986, Shibasaki and coworkers reported catalytic enantioselective Michael addition of malonates to cyclic enones catalyzed by Li-Al bimetallic catalyst (72) (ALB) derived by premixing LiAlH4 and 2 equivalent of (R)-BINOL in THF (Scheme 6.86) [106, 107]. The structure of (R)-ALB was confirmed by X-ray crystallographic analysis of ALB-cyclohexenone complex. One notable advantage of ALB catalyst is that it works nicely in the tandem Michael-aldol sequence. 

The first amine-catalyzed Diels-Alder reaction of a,(i-unsaturated carbonyl compounds as dienes involving in situ enamine activation with chiral amine 29 through raising the diene HOMO energy was accomplished by Barbas and coworkers in 2002 with moderate enantioselectivity (up to 38% ee) [17a]. In 2007, Cordova and coworkers described chiral amine 29 catalyzed enantioselective Diels-Alder reactions between a,P-unsaturated cyclic ketones and nitroolefins with up to 86% ee [17b]. Two years later, Xu and coworkers successfully disclosed a highly efficient enantioselective Diels-Alder reaction of cyclohexenones 31 with aromatic nitroolefins 32 using amine 30 as catalyst in seawater or brine to give products 32 with excellent enantioselectivities (Scheme 38.10) [18a]. Notably, sea water and brine... 

Saa et al. presented remarkable examples for the tri-fluoroacetic acid (TFA)-promoted cyclization of 5, 6, and 7-alkynals (Scheme 24.72). Alkynals 291 having an internal triple bond were converted into the corresponding 5, 6, and 7-membered cyclic enones 293. On the other hand, the cyclization of terminal alkynal 294 afforded the cyclohexenone compound 296. The authors suggested that the observed formation of each enone compound would involve aldol-type reactions of vinyl trifluoroacetate intermediates 292 and 295, formed by the addition of TEA to terminal or internal alkynes, respectively. 

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