3.4- Disubstituted cyclopentanones

Experimental evidence, obtained in protonation (3,6), acylation (1,4), and alkylation (1,4,7-9) reactions, always indicates a concurrence between electrophilic attack on the nitrogen atom and the -carbon atom in the enamine. Concerning the nucleophilic reactivity of the j3-carbon atom in enamines, Opitz and Griesinger (10) observed, in a study of salt formation, the following series of reactivities of the amine and carbonyl components pyrrolidine and hexamethylene imine s> piperidine > morpholine > cthyl-butylamine cyclopentanone s> cycloheptanone cyclooctanone > cyclohexanone monosubstituted acetaldehyde > disubstituted acetaldehyde. 

The formation of an enamine from an a,a-disubstituted cyclopentanone and its reaction with methyl acrylate was used in a synthesis of clovene (JOS). In a synthetic route to aspidospermine, a cyclic enamine reacted with methyl acrylate to form an imonium salt, which regenerated a new cyclic enamine and allowed a subsequent internal enamine acylation reaction (309,310). The required cyclic enamine could not be obtained in this instance by base isomerization of the allylic amine precursor, but was obtained by mercuric acetate oxidation of its reduction product. Condensation of a dihydronaphthalene carboxylic ester with an enamine has also been reported (311). 

Optically active y-alkoxycyclopentenones have become popular in the diastereoselective synthesis of hms-3,4-disubstituted cyclopentanones. The Michael addition to these cyclic enones catalyzed by sodium ethoxide in ethanol277 or by potassium tm-butoxide278 279 proceeds under kinetic control trans with respect to the y-substituent. 

This methodology has been extended to the preparation of 3,3-disubstituted cyclopentanones. The yields and the enantiomeric excess of the final product is heavily dependent on the nature of alkyl groups and the organocopper reagent14. 

The sequence of chiral 1,4-reduction of a fi-substituted cyclopentenone followed by electrophilic trapping of the intermediate enolate provides an efficient route to chiral 2,3-disubstituted cyclopentanones that generates two chiral centers in the process (Eq. 352)459... 

Finally, Lipshutz and co-workers developed catalytic copper(i)-assisted polyfunctionalizations of zirconacyclopen-tenes of type 93 by trapping the intermediary zirconium enolates 94 with an aldehyde to form the corresponding 2,3-disubstituted cyclopentanones 95 (Scheme 40).146... 

The influence of stereocenters in the backbone has been investigated [74]. A racemic substrate 101 can be subjected to standard Stetter reaction conditions leading to disubstituted cyclopentanones 102. The reaction provides both cis and trans diastereomers in high enantiomeric excess but with very poor diastereoselectivity (Table 10). Adding steric bulk did not significantly change the outcome of the reaction (entry 2). The same trend was observed with substitution at the... 

Reaction of 3,3-disubstituted-l,4-pentadiene 92 with a primary amine under cyclohydrocarbonylation conditions yielded cyclopenta[. ]pyrrole 96 as the predominant product accompanied by a small amount of cyclopentanone 95 (Scheme 15). This unique reaction is proposed to proceed through a cascade hydrocarbonylation-carbonylation process. The first hydrocarbonylation of 92 and the subsequent carbocyclization formed cyclopentanoylmethyl-Rh complex 93. If 93 immediately reacts with molecular hydrogen, 2-methylcyclopentanone 95 is formed. However, if CO insertion takes place faster than the hydrogenolysis, cyclopentanoylacetyl-Rh complex 94 is generated, which undergoes the Paal-Knorr condensation with a primary amine to yield cyclopenta[. ]pyrrole 96. ... 

A new method for the synthesis of 2-substituted, as well as 2,4- and 2,5-disubstituted, cyclopentanones in 53-93% yield has been reported.81 For example, the Lewis acid catalyzed transformation of l-propanoyl-l-(4-tolylsulfanyl)cyclobutane gave 2-ethyl-2-(4-tolylsulf-anyl)cyclopentanone (1) in 93 % yield. The formation of the cyclopentanone is best explained by a mechanism which involves initial coordination of aluminum trichloride to the carbonyl oxygen, followed by ring expansion to form the sulfur-stabilized carbocation. Finally, migration of the ethyl group to the carbocation center regenerates concomitantly the carbonyl function.81... 

Chiral 3,3-disubstituted cyclopentanones. Taber et al have extended a synthesis of cyclopentanones by a rhodium catalyzed intramolecular C—H insertion (11,459) to a synthesis of (+ )-a-cuparenone (3), which contains a chiral quaternary center. Thus the chiral a-diazo-p-keto ester 1, prepared by alkylation of a chiral oxazolidone (11, 379-381) on treatment with Rh2(OAc)4 is converted into 2 in 67% yield. This product is converted in several steps into (+ )-3. 

Aside from the ready preparation of some a,p-disubstituted cyclopentanones, the utility of the cyclopropanone hemiacetal approach has been illustrated by the total synthesis of the methyl ester of 11-deoxyprostaglandin E2 342 15). Towards this end, 1-trimethylsilylbutadiynylcyclopropanol 13, readily available from the cyclopropanone hemiacetal 3 (vide supra, Sect. 2.1, Eq. (6)) was successively treated with dihydro-pyran in CH2C12 in the presence of 10% mol. equiv. of PPTS 101). Desilylation by potassium fluoride in DMF 138), formation of the lithium salt with n-BuLi and condensation with hexanal gave the propargylic alcohol 339 in 64 % overall yield. The... 

The accessibility to 2,3-disubstituted — and 4,5-disubstituted 2-cyclopentanones by this thermal C3 -< C5 ring expansion has been illustrated by the syntheses of dihydrojasmone 92), cis-Jasmone 92) and dicranenone A188). 

The amino groups of ovomucoid, lysozyme, and ovotransferrin were alkylated extensively (40-100%) with various carbonyl reagents in the presence of sodium borohydride. Monosubstitution was observed with acetone, cyclopentanone, cyclohexanone, and benzaldehyde, while 20-50% disubstitution was observed with 1-butanal and nearly 100% disubstitution was observed with formaldehyde. The methylated and isopropylated derivatives of all three proteins were soluble and retained almost full biochemical activities. Recently amine boranes have been shown to be possible alternative reducing agents for reductive alkylation... 

Mono-benzoyldiimides such as 177 behave in a relatively normal manner, reaction with the pyrrolidine enamine of cyclohexanone (or cyclopentanone) giving the oxadiazine 178355 (Scheme 181). Reaction of dimethyl azodicarboxylate with / -disubstituted aldehyde enamines is reported to give the 1,2-diazetidine 179 and hence the aldehyde 180 on hydrolysis356", dibenzoyldiimide gives the oxadiazine 1813566 (Scheme 181). The ethoxycarbonyl aroyl diimide 182 reacts to give oxadiazine 183 exclusively357 (Scheme 182). 

Methyl jasmonate (218) has a //arris-locked, 2,3-disubstituted cyclopentanone structure.297 The synthetic route devised by Sisido and co-workers, outlined in Scheme 34, is direct and requires no isomer separation.298) Reaction of the pyrrolidine enamine of methyl 2-oxycyclopent-l-yl acetate (214) with 3-bromo-2-penta-none in toluene gave 215 after hydrolysis. An intramolecular aldol condensation afforded 216 (note double bond migration) whose epoxidation followed by treat-... 

Disubstituted cyclopentanones. 3,4-Disubstituted-4-pentenals (1) cyclize to cis-3,4-disubstituted cyclopentanones (2) in 50-85% yield in the presence of the Wilkinson complex. In contrast, 2,3-disubstituted-4-pentenals (3) under the same conditions cyclize to /ranj-2,3-disubstituted cyclopentanones (4) in low yield because of concomitant formation of cyclopropanes (5). ... 

Stereoselective addition to an a, -enone. 4-Methylcyclopentenone (1) reacts with this reagent to give the adduct 2 with 97% stereoselectivity. The adduct can be converted into 3,4-disubstituted cyclopentanones with high. stereochemical control at three centers. 

Disubstituted ethylenes undergo oxidation with a skeletd rearrangement. Methylenecyclobutane (17) was oxidized to cyclopentanone via ring expansion (Scheme 3). ... 

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