Mechanistic studies of Ce(IV)-mediated oxidation of beta-dicarbonyls: solvent-dependent behavior of radical cation intermediates

The Ce(IV)-initiated oxidation of synthetically relevant beta-diketones and beta-keto silyl enol ethers was explored in three solvents: acetonitrile, methylene chloride, and methanol. The studies presented herein show that the rate of reaction between Ce(IV) and the substrates is dependent upon the polarity of the solvent. Thermochemical studies and analysis are interpreted to be consistent with transition state stabilization by solvent being primarily responsible for the rate of substrate oxidation. Kinetic investigation of radical cations obtained from oxidations of beta-diketones reveals that a more ordered transition state for the radical cation decay is achieved through the direct involvement of methanol in the deprotonation of the intermediate. In the case of radical cations derived from beta-keto silyl enol ethers, experimental data support a mechanism involving unimolecular decay of the intermediate. Remarkably, radical cations derived from beta-diketones and beta-keto silyl enol ethers are surprisingly stable in methylene chloride.     

Neighboring Group Participation in a Regio- and Stereoselective Chlorination of a Bicyclo[2.2.2]octanone

The zinc chloride-mediated acetylation of the optically active silyl enol ether 2a gave the beta-diketone 3a (48%) together with the regio- and stereoselectively chlorinated compound 4 (27%). The yield of 4 increased to 70% by starting from the O-acetyl derivative 2c. The chlorination most likely occurs via neighboring group participation by the endo acetoxy group.     

Total Synthesis of d,l-Isospongiadiol: An Intramolecular Radical Cascade Approach to Furanoditerpenes

A stereoselective oxidative free-radical cyclization of beta-keto ester polyenes 7 and 19 has been accomplished as a one-step entry to the tricarbocyclic synthons 8and 21 which contain five and six stereogenic centers, respectively. These key synthons possessing an axial carboethoxy group at C-4 were ultimately converted to the spongian skeleton (8--> 14 and 21 --> 25 -->14). The synthesis of d,l-isospongiadiol (3) from the common intermediate 14 was realized after introduction of the 2alpha-hydroxy group in the spongian A-ring via epoxidation of silyl enol ether 28 and subsequent desilylation.     

Abnormal Ito-Saegusa oxidation of TIPS enol ether assisted by a hydroxy group on a side chain

Although Ito-Saegusa oxidation gives defined α,β-unsaturated ketones from silyl enol ether of ketones controlled by the position of the sp² carbon of the silyl enol ether, the formation of a regioisomeric product that was oxidized abnormally was observed. The structural requirements for the substrates, the conditions, and a plausible mechanism are presented.     

Photochemical,thermal, and base-induced access to hydroazulene derivatives via two-carbon ring-enlargement reactions of condensed electrophilic cyclobutenes

Enamines, silyl enol ethers, and beta-keto ester anions derived from bicyclo[3.3.0]octan-2-one efficiently underwent a formal [2 + 2] cycloaddition reaction with DMAD and ethyl propynoate leading to a large variety of electrophilic cyclobutenes. The latter were transformed into polyfunctionalized bicyclo[5.3.0]decane (or hydroazulene) ring systems in high yields by fragmentation of the cyclobutene moiety. These two-carbon ring-enlargement reactions were utilized as a synthetic tool for the construction of a polyfunctionalized hydroazulene derivative that represents a potential precursor of the tricyclic framework of ingenol.     

New approaches toward the synthesis of (D-homo) steroid skeletons using Mukaiyama reactions

New, short, and flexible procedures have been developed for syntheses of steroid and D-homo steroid skeletons. A Mukaiyama reaction between the silyl enol ether of 6-methoxytetralone and 2-methyl-2-cyclopentenone or carvone, with transfer of the silyl group to the receiving enone, gave a second silyl enol ether. Addition of a carbocation, generated under Lewis acid conditions from 3-methoxy-2-butenol, 3-ethoxy-3-phenyl-2-propenol or 3-methoxy-2-propenol to this second silyl enol ether gave adducts, which could not be cyclized by aldol condensation to (D-homo) steroid skeletons. The Mukaiyama-Michael reaction of the silyl enol ether of 6-methoxy tetralone with 2-methyl-2-cylopentenone gave a second silyl enol ether, which reacted in high yield with a carbocation generated from 3-hydroxy-3-(4-methoxyphenyl)propene. Ozonolysis of the double bond in this adduct gave a tricarbonyl compound (Zieglers triketone), which has been used before in the synthesis of 9,11-dehydroestrone methyl ether. A second synthesis of C17 substituted CD-trans coupled (D-homo) steroid skeletons has been developed via addition of a carbocation, generated with ZnBr₂ from a Torgov reagent, to a silyl enol ether containing ring D precursor. The obtained seco steroids have been cyclized under formation of the 8-14 bond by treatment with acid. The double bonds in one of the cyclized products have been reduced to a C17-substituted all trans steroid skeleton.     

Mild and efficient pentafluorophenylammonium triflate (PFPAT)-catalyzed C-acylations of enol silyl ethers or ketene silyl (Thio)acetals with acid chlorides

A pentafluorophenylammonium triflate (PFPAT) catalyst (5 mol %) successfully promoted C-acylation of enol silyl ethers with acid chloride to produce various beta-diketones (12 examples; 62-92% yield). Similarly, C-acylation of ketene silyl acetals or ketene silyl thioacetals (i.e., crossed Claisen condensation) proceeded smoothly to provide not only alpha-monoalkylated beta-keto (thio)esters but also thermodynamically unfavorable (less accessible) alpha,alpha-dialkylated beta-keto (thio)esters in good to excellent yield (38 examples; 60-92% yield).     

Isomerization reaction of olefin using RuClH(CO)(PPh(3))(3)

When methyl 5-(tert-butyldiphenylsilyl)oxy-2-pentenoate was refluxed in toluene in the presence of RuClH(CO)(PPh(3))(3) (5 mol %), double-bond migration took place to afford methyl 5-(tert-butyldiphenylsilyl)oxy-4-pentenoate in high yield. This means that the double bond conjugated with the ester moiety migrates to a deconjugated position by a ruthenium catalyst. We planned to prepare an enol ether from alpha,beta-unsaturated compounds having an ether moiety in a tether using ruthenium-catalyzed isomerization of the double bond. As a result, silyl or benzyl enol ether was obtained from the alpha,beta-unsaturated ester having alcohol protected by the silyl or benzyl group in a tether in high yield. In this reaction, double bond migration of alpha,beta-unsaturated ketone and alpha,beta-unsaturated amide took place to produce deconjugated compounds. Moreover, the double bond of alpha, beta-unsaturated ester having a triple or double bond in a molecule migrated to produce conjugated enyne and diene. On the other hand, treatment of a bis-metalated compound having an alpha, beta-unsaturated ester moiety or the double bond in a tether with RuClH(CO)(PPh(3))(3) gave allyl bis-metalated compound in good yield. These compounds are useful units in synthetic organic chemistry.     

Electrooxidative coupling of furans and silyl enol ethers: application to the synthesis of annulated furans

The preparation of annulated furan systems as key synthetic intermediates through the application of a two-step annulation involving an electrochemical ring closure between a furan and a silyl enol ether has been studied. The reaction was shown to be quite general for the formation of six-membered rings in good yields and was tolerant of a variety of different functional groups. The ring closure was highly stereoselective, leading to the formation of cis-fused systems. Cyclic voltammetry and probe molecules were used to gain mechanistic insight into the reaction. These studies suggested that the key ring closure involved an initial oxidation of the silyl enol ether to a radical cation followed by a furan-terminated cyclization.     

STUDIES ON STEROIDAL PLANT-GROWTH REGULATORS (ⅩⅦ)——A NEW SYNTHESIS OF HOMOBRASSINOLIDE AND (22S,23S)-22,23-EPI-HOMOBRASSINOLIDE

Homobrassinolide (2) and (22S, 23S)-22,23-epi-homobrassinolide (4) were synthesized fromstigmasterol in seven steps respectively in 4.7% and 24.1% overall yields. The ratio of 2 to 4is 1:5. The key step is the highly regioselective formation of the B--homo-7-oxa-lactone ringby oxidation of an enol silyl ether with 3--chloro-peroxybenzoic acid.     

Studies on steroidal plant-growth regulators (XVII)--a new synthesis of homobrassinolide and (22S, 23S)-22, 23-epi-homobrassinolide

Homobrassinolide (2) and (22S, 23S)-22,23-epi-homobrassinolide (4) were synthesized from stigmasterol in seven steps respectively in 4.7% and 24.1% overall yields. The ratio of 2 to 4 is 1:5. The key step is the highly regioselective formation of the B-homo-7-oxa-lactone ring by oxidation of an enol silyl ether with 3-chloro-peroxybenzoic acid.     

A Novel Synthesis of Squaric Acid Esters

A new procedure for the synthesis of the benzylic ester of the squaric acid is described. A first example of the reaction silyl ‘enol ether’ of the squaric acid with an electrophile in the presence of a fluoride source to give an O-alkylated product is described.     

Solvent-dependent chemoselectivities in Ce(IV)-mediated oxidative coupling reactions

The oxidative coupling of 1,3-diketones, beta-keto esters, and beta-keto silyl enol ethers with allyl trimethylsilane in the presence of CTAN was investigated. In the case of acyclic diketones and esters, different chemoselectivities were observed in CH(3)CN and CH(2)Cl(2) leading to good yields of allylation and dihydrofuran products, respectively. [reaction: see text]     

Synthesis of mono- and difluoroacetyltrialkylsilanes and the corresponding enol silyl ethers

A variety of mono- and difluoroacetylsilanes and the corresponding silyl enol ethers were prepared from trifluoroethanol and chlorotrialkylsilanes in the presence of LDA through retro-Brook rearrangement. Sterically demanding silyl groups, especially those bound to oxygen, resulted in higher yields of difluoroacetylsilanes. The yields of difluoroacetylsilanes were also dramatically affected by the method of the termination of the reaction. Difluorohaloacetylsilanes were prepared from the corresponding difluoroethenyl silyl ethers with electrophilic halogenating reagents in good yields. A gamma-fluorinated beta-diketone 9a was prepared from monofluoroacetyltriisopropylsilane by nucleophilic acylation with methyl trifluoroacetate.     

Efficient Ce(NO3)3 x 6H2O-catalyzed solvent-free synthesis of 3,4-dihydropyrimidin-2(1H)-ones

Cerium(III) nitrate hexahydrate efficiently catalyzes the three-component Biginelli reaction under solvent-free conditions of an aldehyde, a beta-keto ester or beta-diketone and urea or thiourea to afford the corresponding 3,4-dihydropyrimidin-2(1H)-ones or -thiones in excellent yields.     

Reactions of novel mono- and difluoroacetyltrialkylsilanes with sulfur and phosphorus ylides

The reactions of difluoroacetyltrialkylsilanes with methylidene triphenylphosphorane and benzylidene triphenylphosphorane are affected by the nature of the silyl substituents giving either the enol silyl ether or normal Wittig product exclusively, or mixture of both. Reactions with Horner-Emmons type ylide gave only the alkene products. Reactions of mono- and difluoroacetyltrialkylsilanes with dimethylsulfoxonium methylide gave the enol silyl ether products exclusively. Conversion of an enol silyl ether to an epoxide was effected with m-CPBA.     

Enantioselective synthesis of beta-hydroxy acid derivatives via a one-pot aldol reaction-dynamic kinetic resolution

[reaction: see text]. Combining dynamic kinetic resolution with an aldol reaction provides access to beta-hydroxy ester derivatives with high enantiomeric purity (up to 99% ee) in a one-pot procedure. Only simple starting materials are required in this enantioselective process, and preformation of a silyl enol ether is not necessary.     

Cyclooctanone synthesis via a formal [6+2] cycloaddition reaction of a dicobalt acetylene complex

An efficient formal [6+2] cycloaddition reaction of a new six-carbon unit with enol silyl ether was developed on the basis of a dicobalt hexacarbonyl propargyl cation species. Under the influence of EtAlCl₂, 6-benzoyloxy-2-(triisopropylsilyloxy)-1-hexen-4-yne-dicobalthexacarbonyl reacted with enol triisopropylsilyl ethers to yield 7-(triisopropylsilyloxy)-3-cyclooctyn-1-one-dicobalthexacarbonyl derivatives in good yield. The reactions with cyclic enol silyl ethers as well as acyclic enol silyl ethers exhibited remarkably high diastereoselectivity.     

The Ireland-Claisen rearrangement as a probe for the diastereoselectivity of nucleophilic attack on a double bond adjacent to a stereogenic centre carrying a silyl group

The E- and Z-silyl enol ethers 4 derived from allyl 3-R-3-dimethyl(phenyl)silylpropanoate (R = Me, Pr(i) and Ph) and the Z-silyl enol ethers 7 derived from 4-R-4-dimethyl(phenyl)silylbut-2-enyl acetate (R = Me and Pr(i)) undergo Ireland-Claisen rearrangements largely in the same stereochemical sense, with C-C bond formation taking place anti to the silyl group in the conformations 22, 23 and 24 in which the hydrogen atom on the stereogenic centre is inside, more or less eclipsing the double bond. The E-silyl enol ether E-7a derived from 4-methyl-4-dimethyl(phenyl)silylbut-2-enyl acetate shows low diastereoselectivity in the alternative sense, probably because C-C bond formation takes place anti to the silyl group in the conformation 26 with the methyl group inside, but the silyl enol ether E-7b derived from 4-isopropyl-4-dimethyl(phenyl)silylbut-2-enyl acetate shows low diastereoselectivity in the normal sense. The E- and Z-silyl enol ethers 33 derived from cis-crotyl 3-phenyl-3-dimethyl(phenyl)silylpropanoate and the E-silyl enol ether 39 derived from trans-crotyl 3-phenyl-3-dimethyl(phenyl)silylpropanoate undergo Ireland-Claisen rearrangements largely in the same stereochemical sense as their allyl counterparts, but with moderately high levels of diastereocontrol in setting up the third stereogenic centre following from chair-like transition structures.     

The mannich reaction-II : Derivatization of aldehydes and ketones using dimethyl(methylene)ammonium salts

Aldehydes and ketones have been converted efficiently to their corresponding Mannich products by various dimethyl(methylene)ammonium salts under a range of reaction conditions. The several methods used to form these derivatives are compared. Excellent approaches to aldehyde derivatives involve treating the enol silyl ether of the carbonyl compound with methyllithium and then an iminium salt, or directly adding the iminium salt to the enol silyl ether. Ketones may be derivatized effectively by treatment with potassium hydride, followed by an iminium salt, or from the enol silyl ether by addition of the iminium reagent. Use of iminium reagents in the Mannich reaction is recommended because the yields are often good and the site of attachment on an unsymmetrical ketone is both predictable and controllable.