Silylketenes formation

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 confusing picture emerges from the stereochemical outcome of the Mukaiyama variation of the aldol addition. The titanium(IV) chloride mediated addition of silylketene acetals to isobutyraldehyde confirms this statement while there is a reasonable correlation between the predominance of the (/t)-silylkctenc acetal 2 over the (Z)-acetal, and the favored formation of the an/t -carboxylic ester over the. svn-product, the pure (Z)-diastereomer displays no syn selectivity26. 

In general, chiral propanoates providing simple diastereoselectivity (in favor of yyn-aldols), combined with a reasonable degree of auxiliary-induced stereoselectivity, are rare. Numerous terpenoid- and carbohydrate-derived propionates do not display satisfactory syn selectivity60. Similarly, the titanium(IV) chloride promoted aldol addition of the following JV-metbylephe-drine derived silylketene acetal leads to the formation of the. mi-adduct in the moderate diastereomeric ratio of 78 22 (syn-adduct sum of the other stereoisomers)61. 

Highly stereoselective formation of. syn-adducts (syn/anti. >95 < 5) results from the titanium(IV) chloride induced addition ofa-unsubsliluled enolsilanes, as well as of the a-dimethyl silylketene acetal, to 2-benzyloxypropanal3. 

The Mukaiyama variation of the aldol reaction also allows 1,3-induced chelation control. Thus, the reaction of the enolsilane or silylketene acetal with (5 )-3-benzyloxybutanal results in both cases in the predominant formation of the cwt/ -adduct (92 8 and 90 10), respectively14. 

The chelation-controlled addition of silylketene acetal, 1-phenoxy-l-trimethylsilyloxyethene, to enantiomerically pure (S)-2-dibenzylaminopropanaI is not easily accomplished. Although the predominant formation of one diastcrcomcr is possible (d.r. 95 5), the reaction is plagued by a low chemical yield9. 

The combination of the enantiomerically pure 7V-methylephedrine derived silylketene acetal l-[(l/ ,2S)-2-dimethylamino-1-phenylpropoxy]-l-triniethylsilyloxy-l-propene with the chiral aldehyde (,R)-3-benzyloxy-2-methylpropanal leads, after reduction with lithium aluminum hydride, to the formation of a single 1,3-pentanediol 9 ( matched pair ). 

The predominant formation of ann -carboxylic esters and thioesters results when the additives 13 or 14 are used to mediate aldol additions of silylketene acetals derived from propionates and propanethioates37. The enantioselective addition of a-unsubstituted esters or thioesters is also feasible with the borane 1437. 

With chiral enol species (/ )-silylketene acetal derived from (1 R,2S)-N-methyl ephedrine-O-propionate, both the aldehyde carbonyl and the ephedrine NMe2 group are expected to bind to TiCU, which usually chelates two electron-donating molecules to form ra-octahedral six-coordinated complexes.25 Conformational freedom is therefore reduced, and the C-C bond formation occurs on the six-coordinated metal in a highly stereoselective manner.18... 

Silylketene acetals and enolsilanes can also undergo conjugate addition to a,/ -unsaturated carbonyl derivatives. This reaction is referred to as the Mukaiyama-Michael addition and can also be used as a mild and versatile method for C-C bond formation. As shown in Scheme 8-34, in the presence of C2-symmetric Cu(II) Lewis acid 94, asymmetric conjugate addition proceeds readily, giving product with high yield and enantioselectivity.75... 

A diazosilene is probably also involved in the photochemical or copper-catalyzed decomposition of bis(diazoacetate) 156 in benzene (equation 36). In both cases, dia-zoketene 157 was the only identified product72. Its formation was explained by the silylcarbene-to-acylsilene-to-silylketene sequence outlined in Scheme 5. Efforts to achieve the N2 extrusion from the remaining diazo function by thermolysis in boiling toluene or by prolonged photolysis resulted only in unspecific decomposition. 

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... 

In many GTP experiments an induction period of up to a half an hour is observed before polymerization begins. This implies that during the induction period some inhibitor is being consumed or that some intermediate is formed that is the true initiator. In an associative process straightforward formation of catalyst/silylketene acetal complex should not require an induction period. On the other hand, in a dissociative process the catalyst first has to make a small amount of enolate. 

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. 

The preferred formation of the kinetically favored (Z)-silylketene acetal with amide bases in THF can be rationalized by a cyclic transition state model (128) that enables a close interaction between Li cation, carbonyl oxygen and base (Scheme 23). The presence of additives such as HMPA or DMPU results in a greater degree of solvation of the lithium cation and a weakened Li -caibonyl oxygen interaction. Accordingly, the association between base and ester is diminished and the 1,3-diaxial strain in transition state (129) is reduced, whereas transition state (128) is still destabilized by A -strain." In the presence of a slight excess of ester in the enolization mixture, a kinetic resolution process accounts for an additional increase in the ratio of the ( )- vj. the (Z)-lithium enolate (Table 3). ° ... 

Table 3 Effect of Ester to Base Ratio on Stereoselectivity in Silylketene Acetal (SKA) Formation of Ethyl...

Silylketene acetal (154) was directly prepared from a-silyl ester (153) in xylene at 230 C to give after acid hydrolysis the desired stereoisomer (155) in 72% overall yield with 6 1 stereoselectivity. Silylketene acetals are also obtained by TMS-Cl accelerated conjugate addition of cuprates. The latter method suffers presently from low diastereoselectivities, though it offers the attractive possibility of one-pot formation of two carbon-carbon bonds and three contiguous chiral centers (equation 15). 

Ireland rearrangement of the unsaturated macrolide (288) in THF/HMPA (3 1), followed by desilyl-ation in aqueous hydrogen fluoride in acetonitrile, led in 70% yield to a 72 28 mixture of acids (289) and (290) (Scheme 51). The intermediate silylketene acetal was found to be a single isomer, therefore both transition states (291) and (292) seem to participate in product formation (Figure 6). 

For a highly stereoselective formation of silylketene acetals from esters and trialkylsilyl perchlorates see C. 

In the enantioselective total synthesis of p-lactone enzyme inhibitor (-)-ebelactone A and B, I. Paterson and coworkers constructed seven stereocenters and a trisubstituted alkene plus a very sensitive p-lactone ring. The backbone of their strategy applied an aldol reaction / Ireland-Claisen rearrangement sequence and used minimal functional group manipulation. The Ireland-Claisen rearrangement was performed in the presence of an unprotected ketone moiety and set a precedent for this protocol. The diastereoselectivity was 96 4, indicating highly ( )-selective silylketene acetal formation. 

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. 

A comprehensive review article on 3-lactam formation via the ester enolate-imine condensation has been written by Hart and Ha. Achiwa and coworkers have published a full paper detailing their work on the synthesis of N-benzyloxy-3-lactams utilizing the reaction of N-benzyloxyimines with silylketene acetals in the presence of TMS-OTf, or with lithium ester enolates. ... 

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