Cyclohexenone derivatives

A 2-cyclohexenone derivative can be transformed into the corresponding epoxy tosyl-hydrazone by sequential treatment with peracid and tosylhydrazine. The elimination of nitrogen and p-toluenesulfinate and fragmentation after rearrangement to the 3-tosylazo allylic alcohol may occur under mild conditions. Carbonyl compounds with 5,6-triple bonds are formed in high yields (J. Schreiber, 1967 M. Tanabe, 1967). If one applies this reaction to a 9,10-epoxy-1-decalone, a ten-membered 5-cyclodecyn-l-one ring is formed (D. Felix, 1971). This product is an important intermediate in the perfume industry and has been used on a large scale. For this purpose Eschenmoser developed a synthesis in which the readily removed styrene was split off instead of a sulfmic acid. Thus a l-amino-2-phenylaziridine hydrazone was used instead of a tosylhydrazone (D. Felix, 1968). ... 

Keywords 1,4-pentadiene derivatives, 2-cyclohexenone derivatives, di-7i-mcthanc rearrangement, photoirradiation... 

The only 1,1-enediamines known to react with acyclic dienes in an all-carbon [2 + 4]-cycloaddition are the alkylideneimidazolidines, as has been reported by Heuschmann and Gruseck165,166 in recent years. Thus, cycloaddition products are formed at or below room temperature when 3 is treated with 2,4-dienoates. Hydrolysis of cycloadducts 212 by dilute acid leads to 2-cyclohexenone derivatives 215 or their enol tautomers 216 via 213 and 214 (Scheme 11). The reaction has been extended to... 

Inokuchi, T., Okano, M., Miyamoto, T. Catalyzed Diels-Alder Reaction of Alkylidene- or Arylideneacetoacetates and Danishefsky s Dienes with Lanthanide Salts Aimed at Selective Synthesis of cis-4,5-Dimethyl-2-cyclohexenone Derivatives. J. Org. Chem. 2001,66, 8059-8063. 

Startg. m. allowed to react with 2.2 equivalents Na in liq. NH3 and 1 equivalent ethanol, the resulting crude 1,4-dihydropyridine deriv. treated 3 hrs. at room temp, with 3 equivalents aq.-ethanolic NaOH, and the product obtained after deacetalization by aq. HCl at 45° 2-cyclohexenone deriv. Y 90%. S. Dani-S. Danishefsky and A. Nagel, Chem. Commun. 1972, 373, 374. 

An early example of protein engineering of an OYE pertains to the reductase from S. pastorianus as a catalyst in the stereoselective reduction of hulky 3-aIkyl-suhstituted 2-cyclohexenone derivatives in the presence of an NADPH regeneration system [35]. 

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. 

The synthesis of cyclohexenone derivatives by Michael addition followed by intramolec ular aldol condensation is called the Robinson annulation, after Sir Robert Robinson who popularized its use By annulatwn we mean the building of a ring onto some start mg molecule (The alternative spelling annelation is also often used)... 

Maier, W., K. Hammer et al. (1997). Accumulation of sesquiterpenoid cyclohexenone derivatives induced by an arbuscular mycorrhizal fungus in members of the Poaceae. Planta 202(1) 36—42. 

Maier, W., B. Schneider et al. (1998). Biosynthesis of sesquiterpenoid cyclohexenone derivatives in mycorrhizal barley roots proceeds via the glyceraldehyde 3-phosphate/pyruvate pathway. Tetrahedron Lett. 39(7) 521-524. 

Vierheilig, H., H. Gagnon et al. (2000). Accumulation of cyclohexenone derivatives in barley, wheat and maize roots in response to inoculation with different arbuscular mycorrhizal fungi. Mycorrhiza 9(5) 291-293. 

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

Cyclization reactions of vinyl- and alkynylsilanes have been reviewed100. The course of the reaction of the cyclohexenone derivative 184 depends on the catalyst employed ethylaluminium dichloride gives solely the product 185 of 1,6-addition, whereas tetrabuty-lammonium fluoride yields a mixture containing 69% of the 1,4-adduct 186 and 31% of the bridged compound 187 (equation 89)101. Intramolecular addition reactions of allylic silanes102 may also be catalysed by Lewis acids (equation 90) or fluoride ions, and in this case an allyl anion or a pentavalent silicon intermediate may be involved (equation 91). Such reactions are exemplified by the formation of a 1 5 mixture of the diastereomers 189 and 190 when the cyclohexenone derivative 188 is treated with ethylaluminium dichloride (equation 92). In the presence of fluoride anion the ratio of the isomers is reversed103. 

Addition of Lewis acids may not only accelerate the reaction rate of a conjugate addition but may also alter the stereochemical outcome of a cuprate addition. Interestingly when the 6-t-butyl-substituted cyclohexenone derivative 17 was exposed to dibutylcuprate, followed by silylation of the resulting enolate, the cis enol ether 18 was obtained (Scheme 6.3) [8]. If, however, the cuprate addition was performed in the presence of chlorotrimethylsilane, the stereochemical outcome of the conjugate addition reaction was reversed to give trans enol ether 19. 

A particularly important example is the Robinson annulation, a procedure which constructs a new six-membered ring from a ketone.83 84 The reaction sequence starts with conjugate addition of the enolate to methyl vinyl ketone or a similar enone. This is followed by cyclization involving an intramolecular aldol addition. Dehydration frequently occurs to give a cyclohexenone derivative. Scheme 2.10 shows some examples of Robinson annulation reactions. 

Ring contraction of cyclopentenone and cyclohexenone derivatives to cyclobutanes was observed during direct irradiation of various j5,y-unsaturated cyclohexenones. By way of a Nor-rish type I cleavage in n,7i excited singlet (5t) and n,7t excited triplet (T2) states, an acyl/allyl diradical is formed which recombines in the allyl position to form the product of a 1,3-acyl migration,102 while sensitized irradiation leads mainly to oxa-di-rr-methane rearrangement (see Section 4.2.3.). 

Reaction of (30) with diethyl sodiomalonate gives exclusively complex (94), which can be demetal-lated to give the cyclohexenone derivative (95 Scheme 13) in good overall yield.27 A range of nucleophiles can be used, including cyanide, and keto ester enolates, giving, e.g. (96) or (97 Scheme 13), respectively. 

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. 

Stereoelectronic effects should also play an important role in the nucleophilic 1,4-additions of anions to conjugated systems. These effects should therefore influence the Michael reaction as well as the hydrocyanation of a,6-unsaturated ketones. Studies on these reactions provided evidence that the kinetically controlled addition of a nucleophile to a cyclohexenone derivative is indeed subject to stereoelectronic effects. 

Most remarkable is the fact that this method allows the synthesis of interesting cyclohexenone derivatives which are functionalized in the 5-position. Direct functionalization of the 5-position starting from cydohexenones is unknown, to the best... 

Glomus intraradices, Glomus mosseae, and Gigaspora rosea leads to the accumulation of similar cyclohexenone derivatives (Vierheilig et al., 2000). However, no fungus-specific induction of these compounds are known. Pathogens and endophyte did not induce the formation of cyclohexenone derivatives in barley roots (Maier et al., 1997). The role of cyclohexenone derivatives in disease resistance is unknown. 

Colonization of barley, wheat and maize and rice roots by Glomus intraradices resulted in strong induction of transcript levels of the pivotal enzymes of methylerythritol phosphate pathway of isoprenoid biosynthes i.e., 1 -deoxy-D-xylulose 5-phosphate synthase (DXS) and 1 -deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) (Walter et al., 2000). At the same time six cyclohexenone derivatives were characterized from mycorrhizal wheat and maize roots. DXS2 transcript levels are low in most tissues but are strongly stimulated in roots upon colonization by mycorrhizal fungi, correlated with accumulation of carotenoids and apocarotenoids (Walter et al., 2002). Some reports show that the AM symbiosis may cause an increase, decrease, or no change in the plant defense reactions (Guenoune et al., 2001 Mohr et al., 1998). 

Maier W., Schmidt J. Wray V., Walter M.H. Strack D. The arbuscular mycorrhizal fungus Glomus intraradices induces the accumulation of cyclohexenone derivatives in tobacco roots. Planta 1999 207 620-623. 

Another approach involves the use of an electron-poor olefin acting both as an absorbing electron acceptor and as a radical trap. In this case, a PET reaction between a cyclohexenone derivative and a silylated amine led to a radical ion pair. Desilylation of the silyl amine radical cation intermediate in polar protic solvent (e.g., MeOH) and subsequent aminoalkyl radical attack onto the enone radical anion yielded the alkylated cyclohexanones [23]. 

Fukuyama, Ryu and coworkers reported intermolecular [2 + 2]-type cycloaddition of various cyclohexenone derivatives and alkenes using a micro reactor made entirely of glass, which was supplied by Mikroglas (Scheme 4.26) [39]. The device was equipped with a heat exchanger channel system through which water flowed to maintain isothermal reaction conditions. The remarkable photochemical efficiency of this device was manifested in rapid cycloaddition of vinyl acetate to cyclohex-2-enone. With this device, the desired product was obtained in 88% yield after 2 h, whereas the same reaction carried out in a Pyrex flask was very sluggish (only 8%... 

Ketals have also been used as an alternative to link the chiral inductor to the starting reagents. An important asymmetric induction was observed during the cycloaddition of ketals 94 having a C2 axis of symmetry, and a cyclopentenone or cyclohexenone derivative 95. Unfortunately, the observed chemical yields of 96 remain low (Scheme 22) [68]. With ketals of aliphatic enones, the selectivity decreases, and complex mixtures of isomers were observed [69]. 

Scheme 9 Enantioselective [2 + 2] photocyclization of cyclohexenone derivatives iii their host-guest crystals.

The present radical formation was then applied to intramolecular cyclization. 3-Substituted cyclohexenone derivative 64 which has a (tributylstannyl)methylthio group in the side chain was irradiated (hv > 300 nm) in methanol. The desired spiro compound 65 was, however, obtained in low yield (23%) along with methyl sulfide 66 (60%) and dienone 67 (S%). In contrast, when 64 was irradiated in the presence of a 0.3 molar amount of 1,4-dicyanonaphthalene (DCN) as sensitizer in acetonitrile with 5 molar amounts of water, spiro ketone 65 was produced in 84% yield without a detectable amount of 66 and 67. Thus, by employing the DCN-mediated one-electron oxidation, the intramolecular coupling reaction proceeds smoothly (Scheme 27). 

Chiral -substituted ketones Conjugate addition of (CH,)iAI to the kctal (2) of cyclohexenone derived from (S,S)-1 followed by acetylation results in the adduct 3, which is hydrolyzed by acid to (S)-3-mcthylcyclohcxanonc (4) in 77% ee. The ketal derived from (2R,3R)-2,3-butanediol undergoes a similai conjugate addition with low a.symmetric... 

Photohydration of 3-oxo-A -compounds in water-methanol (4 1) gave the corresponding 5a-hydroxy-3-oxo-compounds. ° Photolysis of 3-oxo-4-tosyl-oxycholest-4-ene (204) gave the hydroxy-compound (205) whereas the simple cyclohexenone derivatives (206) afforded the 3-aryl-2-hydroxycyclohexenones (207). It was established that photo-Beckmann rearrangement of A-nor-5a-cholestan-3-one oxime proceeded with retention of configuration at C-5. 

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