Cyclopentanones Michael additions

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. 

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. 

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. 

The above is an example of the Guareschi reaction. It is applicable to most dialkyl ketones and to alicyclic ketones (e.., cj/clohexanone, cyclopentanone, etc.). The condensation product (I) is probably formed by a simple Knoe-venagel reaction of the ketone and ethyl cyanoacetate to yield ethyl a-cyano-pp dimethylacrylate (CH3)2C=C(CN)COOC2Hj, followed by a Michael addition of a second molecule of ethyl cyanoacetate finally, the carbethoxyl groups are converted to the cyclic imide structure by the action of ammonia. 

The Michael addition of (+)-(5 )-51 to the aj3-unsaturated ketone 217 constitutes a key step in the asymmetric synthesis of the optically active cyclopentanone 318, which is precursor of the 11-deoxy-prostaglandins (321). 

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). 

Bicyclic keto esters can easily be prepared by a process called a,a -annulation.29 Thus, treatment of the enamine of cyclopentanone (64) with ethyl a-(bromomethyl)acrylate (98) affords, after work-up, the bicyclic keto ester (99) in 80% yield (equation IS).2911 The mechanism probably involves an initial Michael addition and elimination (or a simple Sn2 or Sn2 alkylation) followed by an intramolecular Michael addition of the less-substituted enamine on the acrylate unit. The use of the enamine of 4,4-bis(ethoxycarbonyl)cyclohexanone (100 equation 26) with (98) gives a 45% yield of the adaman-tanedione diester (101) (yield based on 100 70% when based on 98) via a,a -annulation followed by Dieckmann condensation.29 Enamines of heterocyclic ketones can also serve as the initial nucleophiles, e.g. (102) and (103) give (105) via (104), formed in situ, in 70% yield (Scheme 11 ).29>... 

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. 

The preceding synthesis realized by Paquette provides (-i-)-asteriscanolide in 13 steps starting from protected 2-bromo-4,4-dimethylcyclopentenone (2) in an overall yield of 4 %. The key steps are the convergent merging of the readily available enantiopure cyclopentanone sulfoxide 3 and the methyl 4-hydroxybutynoate 14 This domino Michael-Michael addition with a heteronucleophile has... 

Several examples have been described on Lewis acid and base catalyzed Michael additions. Cyclopentanone-2-carboxylic acid ethylester was added at room temperature to methyl vinyl ketone using 2 mol% FeCl3 -6 H20 as catalyst yielding > 90% of the addition product (Scheme 11) [31]. Cerium(III) chloride in the presence of sodium iodide [32] and trifluoro-methanesulfonic acid have been used as catalysts as well [33]. 

Fig. 12.20. Michael addition of an enamine (—> enamine D), followed by acidic workup —> 5-ketonitrile C). Since the enamine A is produced from cyclopentanone, the figure shows the second part of a two-step reaction that is an alternative to the base-mediated one-step Michael addition (see Section 13.6.1).

The Michael addition of organometallic nucleophiles to enones in the presence of copper(I) salts produces enolates which on treatment with phenylselenenyl bromide give a-seleno ketones. For example, the reaction of the zirconium enolate of 15 with a mixture of phenylselenenyl bromide and diphenyl diselenide affords a mixture of diastereomeric (2R)- and (2V)-phenylse-leno)cyclopentanones 16 in 50% and 31 % isolated yield, respectively12. The analogous reaction with phenylselenenyl chloride gives only the tram-isomer in 27% yield formation of the cw-product is not observed12. 

The Larock modified Saegusa oxidation conditions were utilized in the total synthesis of ( )-8,14-cedranoxide by M. lhara et al. The main strategy was to apply an intramolecular double Michael addition reaction to assemble the tricyclic cedranoid skeleton. The precursor five-membered enone was prepared in high yield from the corresponding substituted cyclopentanone in two steps. 

Methyl dihydrojasmonate is prepared by Michael addition of malonic acid esters to 2-pentyl-2-cyclopenten-l-one, followed by hydrolysis and decarboxylation of the resulting (2-pentyl-3-oxocyclopentyl)malonate, and esterification of the (2-pentyl-3-oxocyclopentyl)acetic acid [136]. 2-Pentyl-2-cyclopenten-l-one is prepared by an aldol condensation between cyclopentanone and valeraldehyde and subsequent isomerization of the resulting 2-pentylidenecyclopentanone [136a], [136b]. 

The title compound can be prepared by condensing an alkyl a-bromocaprylate with a trialkyl propane-1,1,3-tricarboxylate to give a substituted cyclopentanone. Hydrolysis, decarboxylation, and esterification of the resulting monocarboxylic acid with methanol yields the desired ester [139]. Trialkyl propane-1,1,3-tricarbox-ylates can be prepared by Michael addition of dialkyl malonates to alkyl acrylates. 

In connection with prostaglandin syntheses, Michael additions to cyclopentanones with exo- and endocyclic double bonds have been intensively explored. In all cases protonation of the intermediate occurs in such a way that the side chains end up in the tram position, as exemplified by the following76,78-79 (see also references 77 and 80-83). 

The asymmetric Michael addition of secondary enamines has been reviewed by d Angelo [179]. Some of the more selective examples of this type of reaction are listed in Table 5.8. It is significant that these Michael additions are highly regio-selective, reacting virtually exclusively at the more highly substituted carbon, which affords a,a-disubstituted (quaternary) cyclopentanones, cyclohexanones, furans,... 

In alkenyl- and alkynylcarbene complexes the addition of nucleophiles to the carbene carbon competes with the addition to the 3-carbon of the conjugated C-C multiple bond. [17] The regioselectivity of the addition of amines to alkynylcarbene complexes is temperature dependent 1,2-addition is favoured by lower temperatures. [17c] Enolates turned out to be efficient C-nucleophiles for Michael addition reactions to unsaturated metal carbenes. The product distribution may depend on steric factors as shown in Scheme 7 for the addition of different enolates to alkenylcarbene complex 10. The less bulky acetone enolate 11 adds to the carbene carbon protonation of the primary addition product results in demetalation and in the formation of a mixture of isomeric enones 12. In contrast, the more bulky cyclopentanone enolate 13 adds to the less shielded vinylic position. 

Michael addition, followed by an intramolecular aldol condensation to provide the seven-membered ring. Subsequent retro-Dieckmann reaction, dehydration, and ester saponification provide the bicyclic product in 98% yield. A related cascade reaction was recently reported by the same research group in which the reactions of various allylic halides with cyclopentanone derivatives provide seven-membered rings. ... 

Finally 4-acetoxycyclopent-2-enone (136), acting as a synthetic equivalent for non-existent cyclopenta-2,4-dienone, has been observed to undergo Michael additions, affording fran -disubstituted cyclopentanone derivatives, e.g. (137), capable of subsequent aldol cyclization to rran5-hydroazulene systems, e.g. (138). ... 

Dihydropyran derivatives can be synthesized facilely by a smooth oxidative Mukaiyama-Michael addition followed by a cyclization with silyl enol ethers in the presence of Dess Martin periodinane (DMP) and pyridine under mild reaction conditions from MBH adducts in a one-pot process (Scheme 4.95). Notably, these dihydropyrans were obtained exclusively as cw-isomers in good yields. Moreover, all the reactions worked very well, irrespective of whether MBH adducts were derived from aliphatic or aromatic aldehydes, and silyl enol ethers were derived from acetophenone, cyclohexanone or cyclopentanone. 

Very high enantioselectivities in the PTC Michael addition of 1,3-dicarbonyl compounds to enones have been achieved by Maruoka et al. [189,233] As shown in Scheme 2.86, just a 2 mol% of the binaphthyl-derived phase-transfer catalyst 124b [Scheme 2.70, 124, Ar=3,5-((CFj)jC H3)] in the presence of 10 mol% of solid KjC03, is able to achieved a highly efQdent and enantioselective addition of 2-(9-fluorenoxycarbonyl)cyclopentanone to methyl vinyl ketone [189]. 

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