Annulation cyclopentenone

A combination of an anionic oxy retro-ene and an aldol reaction to give annulated cyclopentenones 4-361 from 4-358 was described by Jung and coworkers (Scheme 4.80) [126]. It can be assumed that, in the presence of KH, the potassium alkoxide 4-359 is first formed this leads to 4-360 and finally to 4-361 in an intramolecular aldol reaction. 

KHAND PAUSON Cycfopentenone Annulation Cyclopentenone synthesis from carbon monoxide acetylene and olefins, cobalt carbonyl catalyzed. 

Also widely used is the combination of a Sonogashira reaction followed by a Pauson-Khandcyclization furnishing annulated cyclopentenones (eq 24). ... 

Several 1,4-dicarbonyl compounds are prepared based on this oxidation. Typically, the 1,4-diketone 10 or the 1,4-keto aldehyde 12 can be prepared by the allylation of a ketone[24] or aldehyde[61,62], followed by oxidation. The reaction is a good annulation method for cyclopentenones (11 and 13). Syntheses of pentalenene[78], laurenene[67], descarboxyquadrone[79], muscone (14 R = Me)[80]) and the coriolin intermediate 15[71] have been carried out by using allyl group as the masked methyl ketone (facing page). 

In addition to the synthesis of heterocycles, the Corey-Chaykovsky reaction bestows an entry to carbocycles as well. The reaction of (trialkylsilyl)vinylketene 89 with substituted ylide 90 led exclusively to rrans-4,5-dimethyl cyclopentenone 91. The substituted ylide 90 here serves as a nucleophilic carbenoid reagent in the formal [4 +1] annulation reaction. 

Whereas, the sulfur ylide 9 undergoes conjugate addition to enones thereby precluding 1,2-cyclopentyl annulation, the organolithium 37a undergoes clean carbonyl addition. Cyclopentenone participates smoothly in this sequence (Eq. 88)81>. 

The availability of cyclopentenones from butanolides allows the lactone annulation to facilitate the synthesis of cyclopentyl natural and unnatural products. An example that highlights the latter is dodecahedrane (178) for which 179 constitutes a critical synthetic intermediate 136,137). Lateral fusion of cyclopentenones as present in 179 can arise by acid induced reorganization and dehydration of 180. While a variety of routes can be envisioned to convert a ketone such as 182 into 180, none worked satisfactorily137 On the other hand, the cyclobutanone spiro-annulation approach via 181 proceeds in 64 % overall yield. Thus, the total carbon cource of dodecahedrane derives from two building blocks — cyclopentadiene and the cyclopropyl sulfonium ylide. 

Bicyclo[4.3.0]nonenes, thanks to their frequent appearance in natural products, are other important targets for novel annulation methodology. A six-membered ring-annulation to cyclopentenones has yet to be developed, the main reason for this being that, until very recently, the levels of enantioselectivity in catalytic 1,4-additions to 2-cyclopentenone were too low for a synthetically useful procedure. However, a highly enantioselective annulation of a five-membered ring to 2-cyclo-hexenone has been developed (Scheme 7.26) [80]. 

The reaction of (trialkylsilyl)vinylketenes with nucleophilic carbenoid reagents, such as sulfur ylides and diazo compounds, has been used for synthesis of substituted cyclopentenones by stereoselective 4 + 1-annulation (Scheme 12). The strategy relies on the remarkable ability of silyl substituents to stabilize ketenes and suppress their tendency to undergo dimerization and 2 - - 2-cycloaddition. 

McKervey and coworkers have developed an elegantly simple pathway for the conversion of m-bicyclo[3.3.0]octane-2,6-dione to (C2)-C2o-hexaquinane diketone 858 (Scheme CII) Twofold cyclopentenone annulation and hydrogenation rapidly led to the tetraquinane 857. Repetition of the same steps then afforded 858, the x-ray analysis of which showed the molecule to have an opened out conformation as the direct result of severe intramolecular overcrowding. 

The synthesis of thiiranes with subsequent elimination of sulfur is an important procedure for the creation of C=C bonds, especially for sterically crowded systems (47,48), in analogy to the Eschenmoser-sulfide-contraction reaction (116). The spontaneous elimination of sulfur was observed in the rhodium-catalyzed reaction of diazo compound 62, which gave rise to the formation of cyclopentenone derivative 63 (117) (Scheme 5.24). A synthesis of indolizomycin was published by Danishefsky and co-workers (118) and involved a similar annulation step. In this case, however, the desulfurization reaction was achieved by treatment with Raney Ni. 

A new synthesis of ( )-actinidine has been reported it is interesting in that it has, as its key step, the thermal intramolecular cycloaddition of an acetylenic pyrimidine.34 A further synthesis of ( )-muscopyridine, based on a regioselective cyclopentenone annulation, has been described.35... 

Likewise, 1,1-dichloroallyllithium preferably reacts C-l with electrophiles63) as is seen from the results of Hiyama et al, who used this reagent for cyclopentenone annulation 64) (Eq. (59)). 

A variety of annulations leading to ring systems other than benzenes can be isolated from reactions of Fischer carbenes. Cyclopentenone derivatives are formed from a reaction of Z-6-amino-Q ,jS-unsaturated chromium carbenes with alkynes (Scheme 66). In contrast, -B-amino-Q, /3-unsaturated chromium carbenes reacts with alkynes to give cyclopentadienes (Scheme 67). 

Both (+)-nootkatone (566) and its (+)-4-isomer (565) have been synthesized from (+)-nopinone (564) (Scheme 69). ° On the other hand, Hiyama et have used a completely different approach for the synthesis of nootkatone (566) (Scheme 70) which involves as a key step the acid-induced cyclopentenone annulation. In an alternative route to eremophilane and valencane sesquiterpenes, NM et have used a stereoselective intramolecular Diels-Alder... 

However, palladium and nickel catalyzed versions promise, at the moment, an even wider range of possibilities. The need to maintain the catalytic cycle by continuous regeneration of the zerovalent metal catalyst limits, nevertheless, the functionalizability of the metallated center in the cyclized intermediate. For the same reason, the readily accessible starting materials may contain various functional groups which are compatible with the reaction conditions and which may be of value for the syntheses of complex heterocycles such as alkaloids. Carbon monoxide insertion reactions of the cyclized a-metal intermediates were shown to afford monocyclic methyl carboxylates and/or annulated cyclopentanones (cyclopentenones) with concomitant stereocontrolled formation of up to four carbon-carbm bonds. 

The utility of the asymmetric fumarate/butadiene addition in synthesis is highlighted by the conversion of the (f ./ )-cyclohexene (313a) (derived from (+)-( 5)-menthol) to enantiomerically pure (-)-bilobalide (317) (Scheme 78). This conversion involves particularly the annulation of a cyclopentenone ring to (313a) at the acylated centers which govern the topicity of the acylation (313a) - (314) and internal Michael reaction (314) (315). Ozonolysis of the cyclohexene moiety sets the stage for the formation... 

A significant advance in the use of Friedel-Crafts acylation of alkenes to prepare divinyl ketones was the employment of vinylsilanes to control the site of electrophilic substitution. Two groups have developed this approach to cyclopentenone annulation using slightly different strategies. In the method described by Magnus the reagent vinyltrimethylsilane (80) is used primarily as an ethylene equivalent (equation 44). The construction of bicyclic systems followed readily as Nazarov cyclization proceeded under the reaction conditions. Tin(lV) chloride was found to be the most effective promoter of the overall transformation. As expected the position of the double bond is thermodynamically controlled. 

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