Cyclization reactions cyclopentenone synthesis

Silyl enol ethers of alkenyl methyl ketones can be efficiently cyclized to cyclopentenones and cyclohexenones by treating them with stoichiometric amounts of palladium acetate244 an example indicating the elaboration of this approach to the synthesis of a reduced benzoxepinone derivative, and the suggested244 mechanism of the reaction, are depicted in Scheme 174. 

In a mechanistically quite different process Ni(CO>4 is the catalyst precursor and the double bond of an allylic halide serves as the alkene component in another cyclopentenone synthesis. Sequential insertion of the alkyne and CO into an initially formed allyl-Ni complex leads to the primary cyclization product, a (2-oxo-3-cyclopenten-l-yl)methylnickel complex (Scheme 4). The final product of the sequence depends on which of several possible reactions of the latter take place. Important features of this reaction have been described in several reviews. " ... 

Nazarov cyclization reaction. Synthesis of cyclopentenones by the acid-catalyzed electrocyclic ring closure of divinyl or allylvinyl ketones available by hydration of divinylacetylenes. 

Aromatic, aliphatic and heterocyclic acid chlorides all give high yields of ketones, [1,4] addition not being observed with a,3-unsaturated acid chlorides. This leads to a potentially very useful synthesis of divinyl ketones since, in contrast to Lewis acid catalyzed acylations of alkenes, under the neutral reaction conditions for the acylation of alkenylstannanes, cyclizations to cyclopentenones do not occur. 

Cyclopentenones. Heathcock et al have developed a cyclopentenone synthesis that involves an intramolecular Wittig-Horner reaction of 3,e-diketo-phosphonates. For example, the reaction of 2 eq. of (1) with the ester(2)inTHF gives the diketone (3), after hydrolysis of the protective group. When treated with sodium hydride in DME at 20°, (3) cyclizes to the cyclopentenone (4) in 80% yield. 

Electron-rich alkynes, including ethoxy(trimethylsilyl)-acetylene, reacted with chromium alkenylcarbene conplexes at — 10°C in acetonitrile in the presence of a stoichiometric amount of Ni(cod)2 with warming to 20 °C over 2 h to afford moderate yields (40-49%) of cyclopentenones (eq 10). This completely stereoselective nickel(0)-mediated [3 + 2] cyclization reaction of chromium alkenyl(methoxy)carbene complexes with both electron-withdrawing and electron-donating substituted alkynes provides a general synthesis of substituted 2-cyclo-pentenone derivatives, important synthons for the construction of more complex molecules. ... 

While the Pauson-Khand reaction represents a very special cyclopentenone synthesis, our next topic - the metathesis cyclization reaction (MCR) - has the advantage of having a very broad scope in alicyclic as well as heterocyclic chemistry. 

A total synthesis of ( )-aromatin has utilized the lithium anion of the dithiane of (E)-2-methyl-2-butenal as a functional equivalent of the thermodynamic enolate of methyl ethyl ketone in an aprotic Michael addition (Scheme 189) (81JOC825). Reaction of the lithium anion (805) with 2-methyl-2-cyclopentenone followed by alkylation of the ketone enolate as its copper salt with allyl bromide delivered (807). Ozonolysis afforded a tricarbonyl which cyclized with alkali to the aldol product (808). Additional steps utilizing conventional chemistry converted (808) into ( )-aromatin (809). 

Cyclopentenone annelation (cf. 10,444). The reagent undergoes a Nazarov-type cyclization with an a,/S-unsaturated acid chloride to give an annelated 3-phenylthio-cyclopentenone. This reaction was used to prepare the bicyclic cyclopentenone 3, a useful intermediate in synthesis of cyclopentenoid natural products, such as hirsutene (4).3... 

Moreto and coworkers have made improvements to the Chiusoli reaction, the Ni(CO)4-mediated carbonylation cyclization of allyl halides and alkynes, by conducting it in methanol403. It has subsequently been applied in the synthesis of methylenomycin B, in an intramolecular sense to provide bicyclo[3.3.0]octenones, and in intermolecular cases to form both fused bicyclic cyclopentenones and spirocyclopentenones (equations 203 and 204)403-405. 

Ruthenium complexes are also suitable catalysts for carbonylation reactions of a variety of substrates. Indeed, when a reaction leads to C-Ru or het-eroatom-Ru bond formation in the presence of carbon monoxide, CO insertion can take place at the coordinatively unsaturated ruthenium center, leading to linear ketones or lactones. Thus, ruthenium-catalyzed carbonylative cyclization was involved in the synthesis of cyclopentenones by reaction of allylic carbonates with alkenes in the presence of carbon monoxide [124] (Eq. 93). 

In some of these reactions, substantial loss of the enantiomeric excess was observed,but for 1,4-enynes substituted at the propargylic position with a carboxylate (equations 76-78), the reaction proceeds with remarkable transfer of chirality allowing the efficient enantioselective synthesis of cyclopentenones from the corresponding enantiomerically emiched propargylic pivalates. The enantioselectivity can be explained by a remarkable center to helix chirality transfer, which was supported by DFT calculations. " These results indicate that the cyclization is faster than rates of helix interconversion and carboxylate rotation. " ... 

It is well known that ir-allylpalladium complexes (86) are easily formed by the reaction of PdCb with P. y-unsaturated esters or ketones (85). An attempted oxidation of. y-unsaturated esters and ketones with the PdCl2/CuCl/02 catalyst system in aqueous DMF led to ir-allylpalladium complex formation as the main reaction, and the oxidation of the alkenic bond was hardly observed to a significant extent. However, in aqueous dioxane or THF, the oxidation became the main reaction, giving y-keto esters and 1,4-diketones (87), respectively, with high regioselectivity (Scheme 26).Some results are shown in Table 2. In all cases, no P-keto ester or 1,3-diketone was detected. At the end of the reaction, formation of a considerable amount of the ir-allylpalladium complex (86) was observed. y-Keto esters and 1,4-diketones are useful intermediates for Ae preparation of cyclopentanedione and cyclopentenone, respectively, by base-catalyzed cyclization. Tliis regioselective oxidation provides a unique and efficient synthetic method for y-keto ester and 1,4-diketone synthesis. 

The Pauson-Khand reaction is a powerful tool for the synthesis of cyclopentanones, 246, from a>-alkenylacetylenes, 245, and carbon monoxide.176 Enyne cyclization has been catalyzed with nitriles using catalytic (77S-CsH5)2Ti(PMe3)2 95177-179 and other variants have since been discovered where the desired cyclopentenones can be directly prepared from the enyne and CO using (77S-CsHs)2Ti(CO)2 68 (Scheme 33) 176,180-184 Addition of PMe3 to the latter reaction mixture has proved to be beneficial. Stoichiometric reactions established that the initial step in the catalytic cycle is reductive coupling of the alkyne and the olefin to form the titanacycle. Carbon monoxide insertion followed by reductive elimination generates the observed product. 

There has been significant interest in the development of a catalytic asymmetric Pauson-Khand type reaction because of its vast potential in organic synthesis. A boom in research activity in this field has focused in two areas - the development of catalytic Pauson-Khand type cyclizations and of stoichiometric syntheses of optically active cyclopentenones via the Pauson-Khand reaction, including a recent report of the first intramolecular catalytic asymmetric Pauson-Khand type cyclization. In this review, the existing catalytic systems will be briefly surveyed followed by a detailed analysis of the asymmetric variant. The stoichiometric syntheses of optically active cyclopentenones will also be discussed. 

Irie and co-workers have reported a synthesis of ( )-tecomanine (55) based on a cyclopentenone annulation of 1,4-diketones (Scheme 17) (205). Treatment of 1,3-dimethylpiperidone (246) with lithium diisopropylamide (LDA) and 2-nitro-2-butene, and reaction with 10% hydrochloric acid (Nef reaction) afforded the substituted piperidine 1,4-diketone 247 (a homolog of 230 in Scheme 14) in 87% yield. Reaction of the mixture of isomers with K3PO4 at 55°C for 55 h gave a single cyclized product 248, whose... 

Acylations by a,3-unsaturated acyl halides provide routes to a,3,a, 3 -unsaturated ketones. Care must be taken in choice of reaction conditions, since Lewis acids are excellent catalysts for Nazarov cy-clizations to cyclopentenones (Scheme 2). Indeed, this can be exploited as a synthesis of the five-mem-bered ketones without isolation of the intermediate divinylic ketones. Cyclizations are also observed after acylations of cyclohexenes with vinylacetyl chloride derivatives (equation The acylation-cycloalkylation sequence provides a complement for the Robinson annelation, since the carbonyl function is located adjacent to the bridgehead position. This potential has been realized in natural product syntheses. ... 

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