Cyclopropanes Siloxycyclopropanes

Longifolene has also been synthesized from ( ) Wieland-Miescher ketone by a series of reactions that feature an intramolecular enolate alkylation and ring expansion, as shown in Scheme 13.26. The starting material was converted to a dibromo ketone via the Mr-silyl enol ether in the first sequence of reactions. This intermediate underwent an intramolecular enolate alkylation to form the C(7)—C(10) bond. The ring expansion was then done by conversion of the ketone to a silyl enol ether, cyclopropanation, and treatment of the siloxycyclopropane with FeCl3. 

In 1977, an article from the authors laboratories [9] reported an TiCV mediated coupling reaction of 1-alkoxy-l-siloxy-cyclopropane with aldehydes (Scheme 1), in which the intermediate formation of a titanium homoenolate (path b) was postulated instead of a then-more-likely Friedel-Crafts-like mechanism (path a). This finding some years later led to the isolation of the first stable metal homoenolate [10] that exhibits considerable nucleophilic reactivity toward (external) electrophiles. Although the metal-carbon bond in this titanium complex is essentially covalent, such titanium species underwent ready nucleophilic addition onto carbonyl compounds to give 4-hydroxy esters in good yield. Since then a number of characterizable metal homoenolates have been prepared from siloxycyclopropanes [11], The repertoire of metal homoenolate reactions now covers most of the standard reaction types ranging from simple... 

The carbenoid from Et2Zn/CH2I2 [17], particularly when generated in the presence of oxygen [18], is more reactive than the conventional Simmons-Smith reagents. The milder conditions required are suitable for the preparation of 1-[16, 19] or 2-alkoxy-l-siloxycyclopropanes [20], which are generally more sensitive than the parent alkyl substituted siloxycyclopropanes (Table 2). Cyclopropanation of silyl ketene acetals is not completely stereospecific, since isomerization of the double bond in the starting material competes with the cyclopropanation [19]. 

Treatment of zinc homoenolates with Me3SiCl in a polar solvent also results in cyclopropane formation Eq. (23). This provides a very mild route to the siloxycyclopropanes [24]. 

Heterosubstituted cyclopropanes can be synthesized from appropriate olefins and car-benes. Since cyclopropane resembles olefins in its reactivity and is thus an electron-rich car bo-cycle (p. 76ft). it forms complexes with Lewis acids, e.g. TiCL, and is thereby destabilized This effect is even more pronounced in cydopropanone ketals. If one of the alcohols forming the ketal is a silanol, the ketal is stable and distillable. The O—Si-bond is cleaved by TiCl4 and a d3-reagent is formed. This reacts with a -reagents, e.g. aldehydes or ketals. Various 4-substituted carboxylic esters are available from 1-alkoxy-l-siloxycyclopropanes in this way (E. Nakamura, 1977). If one starts with l-bromo-2-methoxycyclopropanes, the bromine can be selectively substituted by lithium. Subsequent treatment of this reagent with carbonyl compounds yields (2-methoxycyclopropyl)methanols, which can be transformed to /7,y-unsaturated aldehydes (E.J. Corey, 1975B). 

The mild cleavage conditions with NEt3 HF, which do not cause epimerization at centers a to the carbonyl group, are essential for an enantioselective synthesis of y-oxoesters using optically active catalysts 641 in the cyclopropanation step. Up to 50 % ee have been obtained so far 65). Improvements should be possible, if the trans/cis-ratio of the siloxycyclopropane can be increased. Formylesters of type 99 are promising building blocks for further transformations (e.g. synthesis of y-butyrolactones). 

For the introduction of further substituents at C-l of methyl 2-siloxycyclopropane-carboxylates 97 the deprotonation and smooth alkylation of the resulting enolates is a very feasible route (Eq. 33) 68). It opens the way to a large variety of cyclopropanes without the necessity of preparing a new diazo compound for every desired substituent at C-l. 

Eq. 52 and 53 demonstrate remarkable characteristics of this [3 + 2]-cycloaddition starting with a pure diastereomer 130, two stereoisomeric cyclopentanes 131 are obtained. This stereorandom outcome is most simply rationalized assuming a stepwise mechanism with a 1,5-zwitterion as an intermediate in the cycloaddition. The vinylcyclopropane 132 only gives five-membered ring products 133 and no cyclo-heptene derivative, which would result from a conceivable [5 + 2]-cycloaddition. Less activated olefins or cyclopropanes do not undergo a similar [3 + 2]-cycloaddition. Due to the specific substitution pattern, the cyclopentane formation from these siloxycyclopropanes is of no preparative value. 

The synthesis of dihydrofuran derivatives such as 177 has been performed to explore scope and limitations of the Lewis acid promoted hydroxyalkylation of siloxycyclopropanes. Table 6 shows that aromatic as well as aliphatic ketones can efficiently be incorporated. Enolization of ketones does not occur and a 1-methyl group at the cyclopropane is no obstacle for the reaction, which now binds the carbonyl compound to a quartemary center with surprisingly high efficiency (entry 5). Albeit there are some restrictions with regard to the substitution pattern of the cyclopropanes, bicyclic siloxycyclopropanes also give good yields (e.g. entry 6 and Eq. 76). Further examples of the tetrahydrofuran synthesis from intermediate y-lactols with... 

Contrary to the common electrophilic attack at the least substituted cyclopropane carbon, the higher substituted C-C bond is cleaved under these oxidative conditions. Reaction of siloxycyclopropanes with silver (I) or copper (II) tetrafluoroborate leads to 1,6-diketones (equation 73) . Here, electrophilic opening and oxidative dimerization must be assumed. 

Another approach to acceptor-substituted siloxycyclopropanes has recently been described Here, a 1,3-dicarbonyl compound is converted to the corresponding p-trimethylsiloxy a, ) -unsaturated ketone or ester. Cyclopropanation and ring-opening gives 1,4-dicarbonyl compounds, however, conversions and yields are moderate. 

Again, much efficiency was gained by switching from alkoxy to siloxycyclopropanes . Dibromocarbene addition to silyl enol ethers generates cyclopropanes which open to a-bromo a,j5-unsaturated carbonyl compounds on thermolysis or treatment with acid in methanol (equation 137) . It has been shown that this homologation process also works for siloxycyclopropanes obtained by addition of other carbenoids (equation and that it is useful for terpene preparation . ... 

Siloxycyclopropanes are quantitatively converted into )5-acetoxymercuriketones by reaction with mercuric acetate. Successive treatment with PdCl2 or PdCl2 + CO gives a-methyleneketones or y-ketoesters, respectively. The ring cleavage takes place highly selectively at the least substituted cyclopropane carbon atom (equation 60) . 

Treatment of siloxycyclopropanes with acid under more forcing conditions results in further conversion of the initially formed cyclopropanols into the corresponding carbonyl compounds. For example, reaction of l-trimethylsilyl-l-(trimethylsiloxy)cyclopropane (3) with one equivalent of trifluoroacetic acid at 0°C for 15 minutes affords 1-(trimethylsilyl)cyclopropanol (5). Additional reaction for 24 h at 25°C gives ring-opened l-(trimethylsilyl)propan-l-one (4) in 78% yield after vacuum distillation. Desilylation of 3 to the cyclopropanol 5 can also be induced by fluoride ion. ... 

The palladium-catalyzed system can be extended to the acylation of siloxycyclopropanes with aroyl chloride/carbon monoxide or aryl triflate/carbon monoxide, which gives 1,4-diketones. Contrary to the case of doubly oxygen-substituted cyclopropanes vide infra), the acylation of 1-siloxycyclopropanes is restricted to aroyl chlorides and is not applicable to aliphatic or a, -unsaturated acyl chlorides. For the reactions with aryl triflates, tetrakis(triphenylphos-phane)palladium(O) is used as catalyst, while the reactions with aroyl chlorides employ bis(triphenylphosphane)palladium(II) chloride and ( / -allyl)chloropalladium dimer/triphenyl phosphite as catalysts. In these reactions, aroylpalladium(II) species may undergo ring opening of the siloxycyclopropanes. 

The palladium-catalyzed reaction of 1-alkoxy-l-siloxycyclopropanes with carbon monoxide gives 1,4,7-tricarbonyl compounds in good yield. The reaction is rationalized by formation of a /6-palladio ester from the cyclopropane and a palladium(II) salt, which then undergoes... 

Palladium-catalyzed arylative and acylative ring openings (vide supra) can be successfully applied to 1-alkoxy-l-siloxycyclopropanes. Thus, ) -arylated esters and 4-oxo esters, respectively, are synthesized. Yields are generally higher and the reaction conditions milder for doubly oxygen-substituted cyclopropanes than for siloxycyclopropanes. For acylation, the procedure can be extended from aroyl chlorides to aliphatic acyl chlorides and carbon monoxide is no longer necessary for successful acylation. 

Palladium(II) salts catalyze the rearrangement of 1-allyloxy-l-siloxycyclopropanes to provide a mixture of hexenoic acids. The rearrangement proceeds via a double-bond isomerization followed by a ring opening of cyclopropane rather than homo-Claisen rearrangement. 

On the other hand, transition metal mediated conversions of heterofunctionalized cyclopropane derivatives can be used in the generation of three-carbon building blocks. Thus, starting from hydroxy- or siloxycyclopropanes and similar compounds, metal homoenolates can be generated and transformed in the presence of transition-metal complexes. ... 

Numerous other examples for the conversion of oxygen functionalized cyclopropanes with electrophiles in the presence of transition-metal complexes have been reported. 1-Vinyl-or 1-acetylenyl-substituted siloxycyclopropanes in similar conversions lead to cyclopentanone derivatives. Hydroxycyclopropanes with enolates give other l,n-diketones in inter- and... 

The cyclopropane o--bond behaves as a 7r-component in the Pd(II)-catalyzed Ireland-Claisen-type rearrangement, since the strained o--bond of cyclopropane has the high p-character in hybridization. 1-Allyloxy-l-siloxycyclopropane 73 smoothly rearranged in the presence of PdCl2(PhCN)2 catalyst at room temperature. The products after hydrolysis were 74 (59%), 75 (34%), and 76 (4%) (Scheme 30). However, 73 did not undergo the thermal rearrangement even after heating at 150-160 °C for several hours. 

The rearrangement of 1-allyloxy-l-siloxycyclopropanes provided a mixture of hexenoic acids, which could be hydrogenated to provide saturated alkanoic acid (eqs 96 and 97). It is believed that the nucleophilic carbometallation was triggered by the ring expansion of the cyclopropane unit. 

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