Cyclopentanone, -substituted synthesis

Cyclopentanones. Substituted cyclopentanones are formed on treatment of l-acyl-l-(alkylthio)cyclobutanes with AlCl, AlBr, or I eCl,. Yields range from 55 to 90%. A typical synthesis is shown in equation (I). 

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). 

The prochiral meso form of 2-cyclopenlen-1,4-diol (101) reacts with the (Z)-alkenyl iodide 102 to give the 3-substituted cyclopentanone 103 with nearly complete diastereoselectivity (98 2)[92], The reaction is used for the synthesis of prostaglandin. The alkenyl iodide 102 must be in the Z form in order to obtain the high diastereoselectivity. The selectivity is low when the corresponding (Z)-alkenyl iodide is used[93]. 

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 synthetic problem is now reduced to cyclopentanone 16. This substance possesses two stereocenters, one of which is quaternary, and its constitution permits a productive retrosynthetic maneuver. Retrosynthetic disassembly of 16 by cleavage of the indicated bond furnishes compounds 17 and 18 as potential precursors. In the synthetic direction, a diastereoselective alkylation of the thermodynamic (more substituted) enolate derived from 18 with alkyl iodide 17 could afford intermediate 16. While trimethylsilyl enol ether 18 could arise through silylation of the enolate oxygen produced by a Michael addition of a divinyl cuprate reagent to 2-methylcyclopentenone (19), iodide 17 can be traced to the simple and readily available building blocks 7 and 20. The application of this basic plan to a synthesis of racemic estrone [( >1] is described below. 

An important stage in the synthesis has been reached. It was anticipated that cleavage of the trimethylsilyl enol ether in 18 using the procedure of Binkley and Heathcock18 would regiospecifically furnish the thermodynamic (more substituted) cyclopentanone enolate, a nucleophilic species that could then be alkylated with iodo-diyne 17. To secure what is to become the trans CD ring junction of the steroid nucleus, the diastereoisomer in which the vinyl and methyl substituents have a cis relationship must be formed. In the... 

In conclusion, the longest linear sequence of Yamada s (-)-claenone (42) synthesis consist of 40 steps (6 C/C connecting transformation) with an overall yield of 2.1%. The centrepiece of Yamada s synthetic strategy is the sequence of two Michael additions and a retro-aldol addition to provide a highly substituted cyclopentanone building block (52). 

The structural similarity between claenone (42) and stolonidiol (38) enabled Yamada to exploit an almost identical strategy for the total synthesis of (-)-stolonidiol (38) [40]. A short retrosynthetic analysis is depicted in Fig. 12. An intramolecular HWE reaction of 68 was successfully applied for the macrocyclization. The highly substituted cyclopentanone 69 was made available by a sequence that is highlighted by the sequential Michael-Mi-chael addition between the enolate 53 and the a, -unsaturated ester 70 followed by a retro-aldol addition. However, as is the case for the claenone (42) synthesis, the synthesis of stolonidiol (38) is characterized by numerous functional and protecting group transformations that are a consequence of Yamada s synthetic strategy. 

As an example, this opening was applied to the synthesis of enantiopure 3-substituted cyclopentanones 506 from 2-norbornanones 505 ° (equation 220). The key step on this synthetic route was the Beckmann fragmentation of the oxime 505, promoted by TfaO/ pyridine. 

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... 

S)-(+) -2-(p-TOLU NESULFINYL)-2-CYCLOPENTENONE PRECURSOR FOR ENANTIOSELECTIVE synthesis OF 3-SUBSTITUTED cyclopentanones (2-Cyclopenten-l-one, 2-[(4-methylphenyl)sulfinyl>, (S)-)... 

Michael addition.1 This ketene silyl acetal undergoes Michael addition to a,fl-enones in acetonitrile in the absence of a Lewis acid to afford the corresponding O-silylated Michael adduct in high yield. These O-silyl enolates undergo site-specific electrophilic substitution. This sequence was used for vicinal dialkylation of cyclohexanone (equation I) and of cyclopentanone. It is particularly useful for synthesis of methyl jasmonate and related compounds from cyclopentenone. 

Comins, D. L. LaMunyon, D. H. Chen, X. Enantiopure N-acyldihydropyridones as synthetic intermediates asymmetric synthesis of indolizine alkaloids (-J-205A, (-J-207A, and (-J-235B./. Org. Chem. 1997, 62, 8182-8187. Padwa, A. Muller, C. L. Rodriguez, A. Watter-son, S. H. Alkylation reactions of3-(phenyl-sulfonyl) methyl substituted cyclopentanones. Tetrahedron 1998, 54, 9651-9666. 

On the other hand, lithium enolates derived from substituted endocyclic ketones have largely been exploited in the synthesis of steroids since the regioselectivity of their deprotonation can be controlled and high levels of 1,2- and 1,3-stereoselection occur9,418. The control is steric rather than electronic, with the attack directed to the less substituted ji-face of the enolate for conformationally rigid cyclopentanones, whereas stereoelectronic control becomes significant for the more flexible cyclohexanones. Finally, an asymmetric variant of the formation of a-branched ketones by hydration of camphor-derived alkynes followed by sequential alkylation with reactive alkyl halides of the resulting ketones was recently reported (Scheme 87)419. 

An intramolecular alkylation of a-thionitrile (58) leads to a macrocycle, an intermediate for the synthesis of the sesquiterpene (-)-dihydrogermacrene D (Scheme 29). Alkylation of an a-cyanosulfone followed by reduction gave a-substituted acetonitriles. Cyclization of a 1,3-dibromoalkane with (methylthio)acetonitrile yields a l-cyano-l-(methylthio)cyclobutane, a precursor for the synthesis of cyclopentanones. Reaction of a-(arylthio)nitriles with aryl halides in the presence of LDA and BusP at -78 C affords cyanostilbenes. ... 

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