Alkyne-ketone metathesis

Jin T, Yang F, Liu C, Yamamoto Y. TfOH-catalyzed intramolecular alkyne-ketone metathesis leading to highly substituted five-membered cycUc enones. Chem. Commun. 2009 3533-3535. 

The tricyclic compound 20-C, a potential intermediate for alkaloid synthesis, has been prepared by an intramolecular Diels-Alder reaction of the ketone obtained by deprotection and oxidation of 20-B. Compound 20-B was prepared from 20-A using alkyne-ethene metathesis chemistry. Show the mechanistic steps involved in conversion of 20-A to 20-B. 

We found SbFs in the presence of alcohol-catalyzed alkyne-carbonyl metathesis of substituted phenylalkyne with aldehyde, and it was extended to the cascade reaction combined with the Nazarov cyclization of the formed alkenyl phenyl ketones such as 305 (Scheme 24.75). " In this sequence, an appropriate choice of alcoholic additive is critical for the efficient formation of indanone 306. A combination of intramolecular alkyne-carbonyl metathesis with Nazarov cyclization has been independently reported for the construction of polycyclic enone by Yamamoto et al. "... 

During modei studies for the synthesis of botrydiane sesquiterpene antibiotics, B.M. Trost and co-workers prepared a compiex 1,6-enyne precursor for transition metal catalyzed enyne metathesis reactions. The 1,6-enyne was prepared from a heavily substituted alkynal, which was synthesized via the Eschenmoser-Tanabe fragmentation of an epoxy ketone. The resulting alkynal was unstable, so it was immediately subjected to a Wittig oiefination to afford the desired 1,6-enyne. 

Consider the C2-symmetrical precursor 28, in which both acetoxy groups are homotopic (identical). Desymmetrization by hydrolysis of just one acetyl residue could be readily achieved late in a projected synthesis. This would enable a hydroxyl-directed Simmons-Smith cyclopropanation. Mitsunobu esterihcation (with inversion of configuration) would then set the stage for a concluding alkyne metathesis [39] (Scheme 3.24). This approach does not yet address the formation of the stereogenic center in the middle of the target structure, be it by oxidation to a ketone and stereoselective reduction. 

Under enyne cross-metathesis conditions, the intermolecular reaction of the a,(D-dienes 153, derived from the MBH reaction, with different terminal alkynes 154 afforded triene intermediates that cyclized spontaneously under the reaction conditions to give substituted cis-hexahydro-l/f-indenes 155 (Scheme 4.45), which can be further transformed into steroid analogues via TBS deprotection and oxidation. However, metathesis reactions starting with 156 only furnished trienes 157 [as EfZ) mixtures] and no spontaneous intramolecular cycloaddition occurred. Even at elevated reaction temperatures, trienes 157 cyclized only slowly to give octahydronaphthalene diastereomers. With deprotection of the TBS and subsequent Dess-Martin oxidation, trienes 157 could be converted exclusively into cw-fused 7-substituted 6,7-dehy-drodealone-l-one-lO-carboxylic esters 158 in 50-60% yields. Moreover, c ross-metathesis of TBS-unprotected MBH adduct 159 with alkynes 154 along with treatment with Dess-Martin periodinane (DMP) in one pot could conveniently produce the corresponding bicyclic ketones 160 in moderate yields. ... 

It reacts with ketones to produce methylene derivatives in higher yields than are obtained by the Wittig reaction. It adds to alkynes and to alkenes forming metallocycles. This is a pivotal step in the accepted mechanism for olefin metathesis (p. 373). 

Botta and coworkers have used the enyne metathesis in the synthesis of the enantiopure antifungal agent (5 )-bifonazole 130 [47]. In this work, the diene for the Diels-Alder reaction had to be synthesized from an alkyne. Reaction of alkyne (R)-131 with ethyl vinyl ether, in the presence of catalyst 2-Ru, thus afforded the desired diene 132 (Scheme 17.25) in an excellent yield of 88%. Next, the diene 132 was reacted with methyl vinyl ketone in a Diels-Alder reaction to afford compound 133. Exposure of compound 133 to acid and then DDQ yielded the aromatic product 134, where a newly formed benzene ring had been assembled. Further manipulations, including the formation of the required imidazole ring, allowed for the enantioselective synthesis of (S)-bifonazole 130. 

Stereodefined alkenes are ubiquitous structural motifs in many natural products and pharmaceutics, and, moreover, they serve as a foundation for a broad range of chemical transformations. Nowadays, carbonyl olefination, elimination, alkyne addition, alkenylation, and alkene metathesis constitute the most widely used methods for the stereoselective synthesis of various alkenes [1-3]. Whereas no single method provides a universal solution to stereoselective alkene synthesis, the olefination reactions of aldehydes and ketones with phosphorus-stabilized carbon nucleophiles have enjoyed widespread prominence and recognition owing to their simplicity, convenience, complete positional selectivity, and generally high levels of geometrical control [4-9]. 

In 2008, Jin and Yamamoto [23] reported a useful cascade reaction of ketone-tethered 1,3-enynes (Scheme 4.12). Under rather acidic conditions (AuCl3/3AgSbF ), an initial heteroenyne metathesis is suggested to rationalize the intermediacy of dienone 48, which would undergo a Nazarov reaction to form the cyclopentenone product (i.e., 47). Alternatively, regioselective hydrolysis of the alkyne would probably afford diketone 49, which could yield 48 via intramolecular aldol reaction and dehydration. Some adventitious H O might be sufficient, as it is catalytic during the reaction. 

Other computational studies involving NHC-Cu species considered the formation of phenylisocyanates from nitrobenzene, and the development of [3+2] cycloaddition reactions for the formation of 1,2,3-triazoles. In the latter case the use of NHCs allowed the direct use of copper(i) catalysts, whereas copper(ii) precursors were predominant before. With [(NHC)CuBr] the reaction could be run on water and was successful even for internal alkynes, an unusual observation because the intermediacy of Cu-acetylides had previously been assumed. Calculations showed that the [(SIMes)Cu] fragment was ideally set up to bind internal alkynes in an i] -fashion and hence activate them towards cycloaddition. With terminal alkynes the acetylide route may still be operative. Other computational studies on the catalytic activity of [(NHC)Cu] complexes in which the NHC has no particular role but to stabilize the metal by strong o-donation and offer steric protection have been reported, including the activation of CO2 by [(NHC)Cu(EPh3)] (E = Si, Ge, Sn) and the carboxylation of the C-H bond of heteroarenes. The barriers of the two steps of the catalytic cycle of the [(NHC)Cu ]-catalyzed hydrosilylation of ketones have been computed, yet it was shown that the nature of the NHC was not a controlling factor. While the barrier of the hydrocupration step is determined by the nature of the ketone, that of the o-bond metathesis step occurs mainly under electronic control. 

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