Silylketene cycloaddition

Silylketenes in formation of (3-lactones and (3-lactams 98JCS(P1)2105. Syntheses of (3-lactams, (3-lactones, and 1,3- and 1,4-diazetidinediones by pho-tochemically induced cycloaddition reactions of chromium carbene complexes with imines, aldehydes, and azo compounds 97T4105. 

A combined theoretical and experimental study has been reported for the formation of silylated (3-lactams, via Staudinger [2+2] cycloaddition reaction from silylketenes and imines, in the presence or in the absence of a Lewis acid... 

C(2)-C(3) fused polycyclic cephalosporins have received considerable attention as new candidates for /3-lactam antibiotics. An access to tricyclic cephalosporins based on metal-promoted alkenylation of 3-trifloxy-A3-cephem and subsequent Diels-Alder reaction has been published <1996TL5967>. Alternatively, the reaction of a cephalosporin triflate with silyl enol ethers and silylketene acetals has been described to afford tri- and tetracyclic cephalosporins <1996TL7549>. A related process is the formation of fused polycyclic cephalosporins 27 and 28 bearing a wide range of functionalities from the reaction of cephalosporin triflates 26 with unsaturated compounds (alkenes and alkynes) and a base (Scheme 5) <1997JOC4998>. These studies have suggested that the reaction proceeds via the intermediacy of a six-membered cyclic allene which undergoes concerted nZs + K2a cycloaddition with alkenes and acetylenes. 

It has been long established that Lewis acid-catalysed [2+2] cycloaddition of ketenes and carbonyl compounds provides access to 2-oxetanones. In the development of this reaction prior to 1996, there has been a specific focus on controlling the stereochemistry of the /3-lactone product and cycloadditions have been achieved between trimethyl-silylketene and aldehydes with up to 90% stereoselectivity, as discussed in CHEC-II(1996) <1996CHEC-II(1)721>. CHEC(1984) and CHEC-II(1996) also discuss examples of the Lewis acid-catalyzed, nonphotolytic [2+2] cycloaddition of electron-rich alkenes with aldehydes or ketones <1984CHEC(7)363, 1996GHEC-II(1)721>. While this method can have some advantages over the photolytic reaction in terms of regioselectivity, no examples of this reaction have been reported in recent years. 

Cycloaddition Reactions. Bis(oxazoline) copper complexes such as 2 (and its hydrated congener) facilitate the [2 + 2] cycloaddition between silylketenes and glyoxylate/pyruvate esters (eq 18). The reaction is tolerant to various silyl substituents and structural variation on the dicarbonyl reactant. 

Titanium Lewis acids effect formal [2 + 2] cycloaddition as shown in Eqs (158) [401] and (159) [402,403]. Subtly changing the reaction conditions and substrates alters the product of Eq. (159) from the cyclobutane to a dihydrobenzofuran derivative, as will be described below. The analogous hetero [2 + 2] addition of a chiral aldehyde to a silylketene proceeded stereoselectively in the presence of titanium tetrachloride to give the propiolactone, as shown in Eq. (160) [404]. The silyl group was removed by the treatment with KF. 

Lipstatin is a natural product that exhibits potent inhibitor activity of the pancreatic lipase, and therefore it is a potential lead for the development of antiobesity agents. P.J. Kocienski developed a synthesis for this compound that incorporates an aldehyde-ketene cycloaddition as the key step. The reaction between the aldehyde and silylketene derivative was carried out in the presence of EtAICIs that served as the Lewis acid activator. This transformation led to the formation of four diastereomers in 91% yield, but after desilylation, the desired stereoisomer could be isolated in 64% yield from the mixture. 

Assembly of the lipstatin framework is effectively accomplished by a diastereoselective Lewis acid-promoted [2 + 2] cycloaddition reaction between silylketene 1152 and aldehyde 1151. The reaction occurs between —45 °C and —20 °C to give a 9 1 mixture of 1153 and the corresponding C-4 epimer. After desilylation and column chromatography, esterification with ( S)-A-formylleucine under Mitsunobu conditions furnishes (— )-lipstatin (1144). 

Silylketenes are more stable than the parent ketenes and have been used in cycloaddition reactions, particularly with aldehydes to form p-lactones. Cycloaddition of a ketene with an aldehyde normally requires a Lewis acid catalyst, such as AICI3, BF3-OEt2 or ZnCl2 and under such conditions good yields of the P-lactone products can be obtained. For example, cycloaddition of the aldehyde... 

H- 2] Cycloaddition is one of the most convenient methods for the construction of optically active four-membered carbon- or heterocyclic rings that are useful intermediates in organic synthesis. Titanium Lewis acids have been found to promote formal [2 + 2] cycloaddition between two olefins with different electronic features [181]. The analogous hetero [2 + 2] addition of a chiral aldehyde to a silylketene can be catalyzed by TiCU to give the propiolactone with high diastereoselectivity as shown in Scheme 14.80. The silyl group in the product can be easily removed by treatment with KF [182]. 

The asymmetric hetero [2 + 2] cycloaddition of an aldehyde to silylketene was also catalyzed by TADDOL-TiCl2 to give a cis adduct exclusively and the silyl group in the product can be removed by treatment with KF to give P-lactone derivative with 80% ee [186] (Scheme 14.83). 

Reactive Enophile in [4 + 2] Cycloadditions. Vinylketenes are not effective as dienes in Diels-Alder reactions because they undergo only [2 + 2] cycloaddition with alkenes, as predicted by frontier molecular orbital theory. However, silylketenes exhibit dramatically different properties from those found for most ketenes. (Trimethylsilyl)vinylketene (1) is a relatively stable isolable compound which does not enter into typical [2 + 2] cy do additions with electron-rich alkenes. Instead, (1) participates in Diels-Alder reactions with a variety of alkenic and alkynic dienophiles. The directing effect of the carhonyl group dominates in controlling the regiochemical course of cycloadditions using this diene. For example, reaction of (1) with methyl propiolate produced methyl 3-(trimethylsilyl)sahcylate with the expected regiochemical orientation. ProtodesUylation of this adduct with trifluoroacetic acid in chloroform (25 °C, 24 h) afforded methyl salicylate in 78% yield (eq 2). 

Also, reaction of ketene with 4-nitrophenyl trichloroacetophenone at —25°C in the presence of a quinidine catalyst gives the corresponding /3-lactone in 95 % yield (89 % e,e). Ketene reacts with aldehydes in the presence of oxazaborolidine catalysts to give the j3-lactones in an enantioselective manner The enantioselective [2+2] cycloaddition of silylketenes 221 with a-ketoesters affords the cycloadducts 222 in 86-99 % yield (high e,es) . 

Silylketenes undergo a [4+2] cycloaddition reaction with 1,3-dienes and o-quino-dimethanes to give 2-pyranones and isochromenes, respectively. For example, from 382 and silylketene 383 the [4+2] cycloadduct 384 is obtained... 

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