Cyclization Cyclopentanone

Cydopentane reagents used in synthesis are usually derived from cyclopentanone (R.A. Ellison, 1973). Classically they are made by base-catalyzed intramolecular aldol or ester condensations (see also p. 55). An important example is 2-methylcydopentane-l,3-dione. It is synthesized by intramolecular acylation of diethyl propionylsucdnate dianion followed by saponification and decarboxylation. This cyclization only worked with potassium t-butoxide in boiling xylene (R. Bucourt, 1965). Faster routes to this diketone start with succinic acid or its anhydride. A Friedel-Crafts acylation with 2-acetoxy-2-butene in nitrobenzene or with pro-pionyl chloride in nitromethane leads to acylated adducts, which are deacylated in aqueous acids (V.J. Grenda, 1967 L.E. Schick, 1969). A new promising route to substituted cyclopent-2-enones makes use of intermediate 5-nitro-l,3-diones (D. Seebach, 1977). 

Formation of cyclopentanones by cyclization-decarboxylation of adipic acids r COjH... 

The cyclic /3-keto ester produced in a Dieckmann cyclization can be further alkylated and decarboxylated by a series of reactions analogous to those used in the acetoacetic ester synthesis (Section 22.7). For example, alkylation and subsequent decarboxylation of ethyl 2-oxocyclohexanecarboxylate yields a 2-alkylcvclohexanone. The overall sequence of (1) Dieckmann cyclization, (2) /3-keto ester alkylation, and (3) decarboxylation is a powerful method for preparing 2-substituted cyclohexanones and cyclopentanones. 

The intramolecular Michael addition of acyclic systems is often hampered by competing reactions, i.e., aldol condensations. With the proper choice of Michael donor and acceptor, the intramolecular addition provides a route to tram-substituted cyclopentanones, and cyclopentane and cyclohexane derivatives. Representative examples are the cyclizations of /3-oxo ester substituted enones and a,/J-unsaturated esters. 

Esterification of the propionic acid side chain at C-13 (ring C) with a methyl group catalyzed by S-adenosyl-L-methionine-magnesium protoporphyrin 0-meth-yltransferase yields protoporphyrin IX monomethyl ester (MPE), which originates protochlorophyllide by a P-oxidation and cyclization of the methylated propionic side chain. This molecule contains a fifth isocyclic ring (ring E), the cyclopentanone ring that characterizes aU chlorophylls. 

Fernandez-Matess recently demonstrated that nitriles constitute excellent radical traps in titanocene-mediated epoxide openings, even though these cyclizations are considered as being quite slow. As shown in Scheme 31 cy-clobutanones, cyclopentanones, and cyclohexanones can be prepared in high yields [122]. 

Reaction of phenyl vinyl ketone with cyclopentanone under thermal conditions resulted in a diastereomeric mixture of 1,5,9-triketones 374 via a double Michael reaction. Treatment of this mixture with ammonium formate in polyethyleneglycol-200 under microwave irradiation conditions led to the very fast and efficient formation of a 2 1 diastereomeric mixture of cyclopental flquinolizidines 375 and 376 <2002T2189>. When this reductive amination-cyclization procedure was carried out starting from the purified /ra r-isomer of 374, the result was identical to that obtained from the cis-trans mixture, showing the operation of thermodynamic control (Scheme 86). 

As described above, our synthetic strategy involves the convergent construction of the central cyclopentanone ring with a carbonylative cross-coupling reaction and a photo-Nazarov cyclization reaction (Chart 2.2). The electrophilic coupling component 51 was synthesized by an intramolecular Diels-Alder reaction [34] and the nucleophilic coupling component 52 by a vinyiogous Mukaiyama aldol reaction [35]. 

Marchand and co-workers ° synthesis of 5,5,9,9-tetranitropentacyclo[5.3.0.0 .0 °.0 ] decane (52) reqnired the dioxime of pentacyclo[5.3.0.0 .0 °.0 ]decane-5,9-dione (49) for the incorporation of the four nitro groups. Synthesis of the diketone precursor (48) was achieved in only five steps from cyclopentanone. Thus, acetal protection of cyclopentanone with ethylene glycol, followed by a-bromination, and dehydrobromination with sodium in methanol, yielded the reactive intermediate (45), which underwent a spontaneous Diels-Alder cycloaddition to give (46). Selective acetal deprotection of (46) was followed by a photo-initiated intramolecular cyclization and final acetal deprotection with aqueous mineral acid to give the diketone (48). Derivatization of the diketone (48) to the corresponding dioxime (49) was followed by conversion of the oxime groups to gem-dinitro functionality using standard literature procedures. 

In order for C-alkylation to occur, the p orbital at the a carbon must be aligned with the C—Br bond in the linear geometry associated with the SN2 transition state. When the ring to be closed is six-membered, this geometry is accessible, and cyclization to the cyclohexanone occurs. With five-membered rings, colinearity cannot be achieved easily. Cyclization at oxygen then occurs faster than does cyclopentanone formation. The transition state for O-alkylation involves an oxygen lone-pair orbital and is less strained than the transition state for C-alkylation. 

Other electron-withdrawing groups are compatible with diazo transfer and cyclization, Both the / -keto sulfone 9 and the /J-keto phosphonate 11 have been cyclized using rhodium acetate catalysis4 8,49. The cyclized keto phosphonate 12 can be further reacted49 with formaldehyde to yield the a-alkylidene cyclopentanone 13. 

While the detailed mechanism of these rhodium-catalyzed cyclizations is not known, a working hypothesis that accommodates all of the observations to date is as follows. The diazo ketone can be considered to be a stabilized ylide, 14. Association of the Lewis acidic LUMO of the rhodium(II) carboxylate with the locally electron-rich ylide yields 15. Loss of nitrogen would then give the highly electrophilic intermediate 16. In nondonating solvents, the richest source of electron density available to this reactive species is the remote C—H bond. Complexation with the electron density in this bond gives 17, which collapses to the cyclopentanone product. 

A powerful feature of intramolecular C-H insertion is the inherent ability to transform an acyclic ternary stereogenic center into a cyclic quaternary stereogenic center26. It has been demonstrated that the rhodium-catalyzed cyclization of methyl (tf)-2-diazo-6-(4-methylphenyl)-3-oxohep-tanoate to cyclopentanone 6 indeed proceeds with retention of absolute configuration61. The absolute configuration of the latter was confirmed by conversion to the sesquiterpene (+ )-a-cu-parenone. 

Cyciopentanones. I hc cyclization of 4-pentenals to cyclopentanones catalyzed by Wilkinson s catalyst (4, 560) has been improved considerably by modification of the phosphine ligands.1 Catalysts containing tri-p-tolylphosphine. tri-p-anisylphos-phine, and lris(p-dimethylaminopheny )phosphine are particularly useful. Simple cyclopentanones can he prepared in high yields. The reaction also provides a route to spirocyclic and bicyclic ketones (equations I and II). Unfortunately this method is not applicable to synthesis of larger rings. 

Certain unsaturated aldehydes may be converted to cyclic ketones by a related mechanism. The formyl group reacts with Rh(I) complexes to form an acyl-Rh hydride species, which undergoes intramolecular reaction with the olefinic linkage present in the same molecule (117a). Asymmetric induction is observed with a chiral diphosphine ligand (Scheme 53) (117b-d). Enantioselective cyclization of 4-substituted 4-pentanals into 3-substituted cyclopentanones in greater than 99% ee is achieved with a cationic BINAP-Rh complex. 

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