Cyclopentanone silyl enolates

The thermal C3 -> 5 ring expansion of 1-siloxy-l-vinylcyclopropanes occurs either from the Z or from the E isomers. It leads to cyclopentanone silyl enol ethers that are able to undergo either further regiospecific alkylation into 2,3-disubstituted cyclopenta-nones 145.209,213 dehydrosilylation into cyclopentenones The overall process constitutes an efficient three-carbon annelation process (equation 129). 

The use of -fhio- and -silylacryloylsilanes switches the reaction mode from [2-1-1] to ]3-i-2] armulation to form cyclopentanone silyl enolates (Scheme 10.226) [588]. The annulation wifh /i-lhioacryloylsilaries might proceed via the delocahzed allylic carbanion 159 whereas a reaction pathway through 1,3-sigmatropic rearrangement of the vinylcyclopropane intermediate 160 has been proposed for/fsilylacryloylsilaries [589]. 

Radical cyclization using acylsilanes is apphcable to the synthesis of cychc silyl enolates by yS-elimination of the a-siloxyalkyl radical intermediate (Scheme 10.234) [603]. 5-Bromo-5-stannyl- and 5-bromo-2-sulfonyl-alkanoylsilanes are cychzed to cyclopentanone silyl enolates with ehmination of the stannyl and sulfonyl groups. 

Reaction of 4a with TiCl4 was carried out in the presence of siloxyalkene 3 as nucleophile and the results are summarized in Table III. In the reaction with ketene silyl acetals 3a and 3e at -78 °C, y-ketoesters 15a and 15e were obtained instead of chloride product 8 which is a major product in the absence of 3. Formation of product 15 is likely to result from trapping of alkylideneallyl cation 5 with 3 at the sp2 carbon. In contrast, the reactions with silyl enol ethers 3f and 3g gave no acyclic product 15, but gave cyclopentanone derivatives 16-18. The product distribution depends on the mode of addition of TiCl4 (entries 4-7). 

Trimethyl(prop-l-en-2-yloxy)silane afforded (3-amino ketone 24u in good yield (Table 5, entry 10). Silyl enol ethers derived from 3-pentanone and cyclopentanone smoothly afforded (3-amino ketones 24v and 24w, respectively (Table 5, entries 11 and 12). Tetrasubstituted silyl enol ethers readily produced the expected products 24x and 24g (Table 5, entries 13 and 14). 

Several examples of Bi(OTf)3-catalyzed Mannich-type reactions with various silyl enol ethers are summarized in Table 12. Silyl enol ethers derived from aromatic and aliphatic ketones were reacted with an equimolar mixture of aldehyde and aniline (Scheme 10). The corresponding (3-amino ketones 27 were obtained in good yields (Table 12, entries 1M-) from aromatic-derived silyl enol ethers, except for the more hindered isobutyrophenone derivative. Silyl enol ethers derived from cyclopentanone or cyclohexanone afforded the (3-amino ketones in good yields (Table 12, entries 5 and 6). 

During the reaction of p-methoxy benzyl alcohol with silyl enol ether 31b, dibenzyl ether 33 was observed as a by-product, which disappeared after prolonged reaction time. In fact, if 33 was used as alkylating reagent, the silyl enol ether 31b was benzylated and the desired cyclopentanone 32e was obtained in a similar yield (Scheme 25). 

Cyclopentanones may also be synthesized from a,/ -unsaturated ketones and diiodo-methane. The ketone is converted to the O-silyl enol, and carbene is added to the enol double bond using the Simmons-Smith reaction (see p. 74f.). Thermal rearrangement of the resulting 1-siloxy-l-vinylcydopropane and add-catalyzed hydrolysis of the silyl enol ether leads to cyclopentanones in excellent yields (C. Girard, 1974). Very high temperatures, however, are needed, and this obviously limits the generality of this rearrangement reaction. 

Michael addition.1 This ketene silyl acetal undergoes Michael addition to a,fl-enones in acetonitrile in the absence of a Lewis acid to afford the corresponding O-silylated Michael adduct in high yield. These O-silyl enolates undergo site-specific electrophilic substitution. This sequence was used for vicinal dialkylation of cyclohexanone (equation I) and of cyclopentanone. It is particularly useful for synthesis of methyl jasmonate and related compounds from cyclopentenone. 

Pd(OAc)2 to give the cyclohexenone 256. In clavulone synthesis, only the silyl enol ether in 257 reacts with Pd(OAc)2 to give the enone 258 [153]. The dehydrogenation can be carried out with a catalytic amount of Pd(OAc)2 using benzoquinone as the reoxidant. Cyclopentenone (260) is prepared from cyclopentanone (259) by using a supported Pd catalyst under 02 atmosphere [154], The enone 261 is converted to the dienone 263 via the dienol silyl ether 262 [155],... 

OL-Methylenecyclohutanones. The reagent reacts regioselectively with activated alkenes (vinyl ethers, silyl enol ethers) to give cyclobutanones. These products undergo ring expansion with diazomethane to cyclopentanones. Both products undergo desilylative elimination in the presence of fluoride ion to form a-methylene ketones. 

Details of the Janda-Chen synthesis were as follows. A tetrahydropyran (THP) linker was attached to the NCPS support enabling attachment of alcohols via THP ether formation. The THP-NCPS resin 1 is derivatized with R-(-F)-4-hydroxy-2-cyclopentanone 2, giving the THP ether-based resin 3, followed by coupling of the C,3 2o fragment by enone-cuprate addition. The cuprate required was generated from the corresponding E-vinyl stannane 4. The resulting enolate was trapped as the silyl enol ether... 

Substituted cyclopentanones are available by pyrolysis of siloxyvinylcyclopropanes and hydrolysis of the intermediate silyl enol ethers, e.g. formation of 6 and 7. ... 

The best alkylating agents for silyl enol ethers are tertiary alkyl halides they form stable carbocations in the presence of Lewis acids such as TiCl4 or SnCl4. Most fortunately, this is just the type of compound that is unsuitable for reaction with lithium enolates or enamines, as elimination results rather than alkylation a nice piece of complementary selectivity. Below is an example the alkylation of cyclopentanone with 2-chloro-2-methylbutane. The ketone was converted to the trimethylsilyl enol ether with triethylamine and trimethylsilylchloride we discussed this step on p. 466 (Chapter 20). Titanium tetrachloride in dry dichloromethane promotes the alkylation step. 

Dihydropyran derivatives can be synthesized facilely by a smooth oxidative Mukaiyama-Michael addition followed by a cyclization with silyl enol ethers in the presence of Dess Martin periodinane (DMP) and pyridine under mild reaction conditions from MBH adducts in a one-pot process (Scheme 4.95). Notably, these dihydropyrans were obtained exclusively as cw-isomers in good yields. Moreover, all the reactions worked very well, irrespective of whether MBH adducts were derived from aliphatic or aromatic aldehydes, and silyl enol ethers were derived from acetophenone, cyclohexanone or cyclopentanone. 

We mentioned that by mixing vinyl epoxides and zerovalent palladium, the alcoholate formed was usually sufficiently basic to deprotonate the pronucleophile entity. In some cases, especially with ketones, low reactivity and yields were reported (Table To overcome the problem of the weak basicity of the alcoholate, silyl enol ethers, keto adds, or preformed lithium enolates have successfully been employed.f f" f f /3-Keto acids are masked enolates via the decarboxylation of the intermediary Tr-allylpalladium ]3-ketocarboxylate complexes. The main limitation of the use of keto adds as pronucleophiles seems to be their low reactivity toward the hindered cyclic vinyl epoxides. In these cases, the cationic n-allylpalladium complex undergoes ]S-elimination. Indeed, the reaction between benzoyl acetic acid and cyclobutadiene monoxide in the presence of Pd(PPh3>4 gives only the corresponding cyclopentanone and acetophenone as the... 

Steric effects of the hexacarbonyldicobalt moiety may be responsible for altered reactivity, notably enhanced stereoselectivity in reactions of adjacent substituents, e.g. formyl groups in aldol condensations. Thus, condensation of trimethylsilylpropy-nal with the silyl enol ether of cyclopentanone gives a 90% yield of the aldol product (eq 50) as a 40 60 erythro threo mixture, whereas reaction of the Co2(CO)6-complexed aldehyde followed by cerium(IV) oxidation gives the same total yield, but in an 87 13 diastereomeric ratio. ... 

Titanium(IV) is a powerful but selective Lewis acid which can promote the coupling of allylsilanes with carbonyl compounds and derivatives In the presence of titanium tetrachlonde, benzalacetone reacts with allyltnmethylsilane by 1,4-addition to give 4-PHENYL-6-HEPTEN-2-ONE. Similarly, the enol silyl ether of cyclopentanone is coupled with f-pentyl chloride using titanium tetrachlonde to give 2-(tert-PENTYL)CYCLOPENTANONE, an example of a-tert-alkylation of ketones. 

The synthetic problem is now reduced to cyclopentanone 16. This substance possesses two stereocenters, one of which is quaternary, and its constitution permits a productive retrosynthetic maneuver. Retrosynthetic disassembly of 16 by cleavage of the indicated bond furnishes compounds 17 and 18 as potential precursors. In the synthetic direction, a diastereoselective alkylation of the thermodynamic (more substituted) enolate derived from 18 with alkyl iodide 17 could afford intermediate 16. While trimethylsilyl enol ether 18 could arise through silylation of the enolate oxygen produced by a Michael addition of a divinyl cuprate reagent to 2-methylcyclopentenone (19), iodide 17 can be traced to the simple and readily available building blocks 7 and 20. The application of this basic plan to a synthesis of racemic estrone [( >1] is described below. 

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