Cyclohexenones, 5-substituted synthesis

Ethoxy-2-cyclohexenone is a useful intermediate in the synthesis of certain cyclohexenones. The reduction of 3-ethoxy-2-cyclohexenone with lithium aluminum hydride followed by hydrolysis and dehydration of the reduction product yields 2-cyclo-hexenone. Similarly, the reaction of 3-ethoxy-2-cyclohexenone with Grignard reagents followed by hydrolysis and dehydration of the addition product affords a variety of 3-substituted 2-cyclo-hexenones. ... 

Carbonyl condensation reactions are widely used in synthesis. One example of their versatility is the Robinson anuulation reaction, which leads to the formation of an substituted cyclohexenone. Treatment of a /3-diketone or /3-keto ester with an a,/3-unsaturated ketone leads first to a Michael addition, which is followed by intramolecular aldol cyclization. Condensation reactions are also used widely in nature for the biosynthesis of such molecules as fats and steroids. 

The third and fourth steps in the synthesis of Hagemann s ester from ethyl acetoacetate and formaldehyde (Problem 23.50) are an intramolecular aklol cyclization to yield a substituted cyclohexenone, and a decarboxylation reaction. Write both reactions, and show the products of each step. 

Using 3-substituted cyclohexanones the /rans-diastereoselective synthesis of decalones and octahydro-1 //-indenones may be achieved 164 169. This method has been applied, for instance, in the synthesis of 19-norsteroids. In a related Michael addition the lithium enolate of (R)-5-trimethylsilyl-2-cyclohexenone reacts with methyl 2-propenoate selectively tram to the trimethylsilyl substituent. Subsequent intramolecular ring closure provides a single enantiomer of the bicyclo[2.2.2]octane170 (see also Section 1.5.2.4.4.). 

The enol ethers of P-dicarbonyl compounds are reduced to a, 3-unsaturated ketones by LiAlH4, followed by hydrolysis.115 Reduction stops at the allylic alcohol, but subsequent acid hydrolysis of the enol ether and dehydration leads to the isolated product. This reaction is a useful method for synthesis of substituted cyclohexenones. 

A simple synthesis of 2-substituted cyclohexenones has been developed. Although the yields are only 25-30%, it is carried out as a one-pot process using the sequence of reactions shown below. Explain the mechanistic basis of this synthesis and identify the intermediate present after each stage of the reaction. 

For a related synthesis of 5- and 6-substituted cyclohexenones see 2,2,6-lrimelhyl-1,3-dioxolenone (this volume). 

The above described total synthesis shows the application of the (7-carbonyl radical-initiated tandem cyclization reaction for the first generation of (+)-paniculatine. With this method starting from 2-substituted-5-(R)-cyclohexenone 5 Sha and co-workers obtained 15 (=1) in 21 steps. Furthermore the HBr-salt of this alkaloid was prepared and subjected to a single X-ray analysis, which unambiguously confirmed the structure and stereochemistry of this synthetic (+)-paniculatine. 

In another study we have constructed a bicyclo[2.2.2]octane library using a tandem Michael addition of enolates of 2-cyclohexenones with various substituted acrylates.7 9 In this way it was possible to prepare a rigid scaffold, from readily available substrates, which could be further elaborated by transformation of the functional groups to give a large array of compounds (Scheme 6). This synthesis required minimal optimisation and... 

For weak acids, the proton is directly transferred from the acid to the substrate in a reagent-controlled manner and, in order to increase the selectivity, extremely shielded 2 -substituted m-terphenyls have been developed as concave protonating reagents inspired by the geometry of enzymes. Thus, the diastereoselective protonation by a series of substituted phenols of endocyclic keto enolates, obtained by the stereocontrolled 1,4-addition of lithiocuprates onto substituted cyclohexenones, was reported by Krause and coworkers354 355 and applied to the synthesis of racemic methyl dihydroepijasmonate356. 

The Hill synthesis 104) of 4-nitro-2,6-diphenylphenol from nitro-malonaldehyde and dibenzylketone was the first example of a useful synthesis by which many similar 2,6-diaryl-substituted cyclohexenone- and 2,6-diarylphenol derivatives have since been prepared. 

The a./y alkylation ratio of the intramolecular nucleophilic substitution reaction of an a,y9-unsaturated cyclohexenone tosylate can also be controlled by the right choice of solvent. The desired y-alkylation - the final step of the total synthesis of the sesquiterpene yS-vetivone - is favoured by NaOH in CH3SOCH3/H2O, in contrast to (CH3)3C0K/(CH3)3C0H, which promotes a-alkylation [670],... 

A definite improvement in the synthesis of A -methoxy aziridines was achieved by substituting boron trifluoride with trimethylsilyl triflate and diethyl ether with dichloromethane"9. In this way, the A -methoxy aziridines were obtained in good yields from a variety of linear and cyclic alkenes, e.g., 6-8. For comparison, the aziridine 8 was obtained in 50% yield by using boron trifluoride- diethyl ether complex in dichloromethane. Complex product mixtures were obtained with allyl and crotyl alcohols and with cyclohexenone. Further transformation of the A -methoxy aziridines into the N-H aziridines was possible using sodium/ ammonia reduction, e.g., 9. 

The intramolecular 1,3-cycloaddition of azidoalkyl cyclohexenones occurred smoothly when the temperature range was between 80-110 °C, however, aziridines were obtained from the intermediate dihydrotriazoles il the correct substitution pattern and regiochemical arrangement were present, cf. formation of 13 and 14 vs. IS131,132. The reaction was applied to the formal total synthesis of ( )-desamylperhydrohistrionicotoxin132. Direct nitrene enone addition can not be ruled out when the reaction is performed in refluxing xylene. 

An efficient use of bicyclic lactams as chiral precursors to 4-substituted cyclopentenones and cyclohexenones has been illustrated by the synthesis... 

The acid fragmentation of suitably substituted bicyclo[2.2.2]octanes to cyclohexenones and subsequent ring closure to spirovetivanes via ir-cation cyclization has been used by Murai for a highly stereoselective isolubimin (56) synthesis. (56) has been considered to play an important role in the bio-genetic pathway of various spirovetivane phytoalexins in the Solanaceae family. Treatment of methyl... 

Chida, N., Ohtsuka, M., Ogura, K., Ogawa, S. Synthesis of optically active substituted cyclohexenones from carbohydrates by catalytic Ferrier rearrangement. Bull. Chem. Soc. Jpn. 1991, 64, 2118-2121. 

Rapson, W. S., Robinson, R. Synthesis of substances related to the sterols. II. New general method for the synthesis of substituted cyclohexenones. J. Chem. Soc. 1935, 1285-1288. 

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