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.     

A novel synthesis of silyl enol ethers from α-silylbenzylthiols and carboxylic acid derivatives via C---C bond formation; thermal rearrangement of S-α-silylbenzyl thioesters

A new procedure for the synthesis of silyl enol ethers from S-α-silylbenzyl thioesters without need for either bases or catalysts via C---C bond formation is described. Solutions of S-α-silylbenzyl thioesters were simply heated at 180°C for 24 h in a sealed tube to give silyl enol ethers in good yields with high stereoselectivity. Cyclization of the dipoles generated by thermal rearrangement of the silyl group and elimination of sulfur afforded silyl enol ethers.     

1,4-silatropy of S-alpha-silylbenzyl thioesters: a convenient route to silyl enol and dienol ethers accompanied by C-C bond formation via thiocarbonyl ylides

A novel convenient method for the generation of thiocarbonyl ylides from readily accessible starting materials and the first synthetic application of in situ generated ylides in the synthesis of silyl enol and dienol ethers, accompanied by C-C bond formation, is described. Under completely neutral conditions without any catalyst or additive, thermal reactions of S-alpha-silylbenzyl thioesters in sealed tubes at 180 degrees C provided silyl enol and dienol ethers in good to excellent yields with high stereoselectivities. This procedure consists of a multistep reaction in a one-pot process, i.e., 1,4-silatropy of S-alpha-silylbenzyl thioesters to give thiocarbonyl ylides, 1,3-electrocyclization of the ylides to give thiiranes, and the extrusion of sulfur from thiiranes to give silyl enol and dienol ethers.     

Metal nitrite: a powerful oxidizing reagent

An efficient and simple source of nitroso reagents and their oxidation reactions are described. The combination of a Lewis acid and a metal nitrite was applied to the oxidation of silyl enol ethers. Amino acid and peptide derivatives were easily accessed through in situ C-C bond cleavage of fully substituted silyl enol ethers upon oxidation.     

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.     

Ligand-induced control of C-H versus aliphatic C-C migration reactions of Rh carbenoids

The reaction of lithiated trimethylsilyldiazomethane (LTMSD) with aldehydes and subsequent quenching with TMSCl furnished relatively stable alpha-silylated diazocompounds. Upon treatment of the alpha-silylated diazocompounds with Rh2(OAc)4 in refluxing toluene, alpha-silyl silyl enol ethers were formed from unbranched and branched aliphatic aldehydes through predominantly 1,2-migration of the C-H bond. In contrast, treatment of the alpha-silylated diazocompounds with Rh2(tfa)4 at room temperature gave alpha-silyl silyl enol ethers through exclusive and unusual 1,2-migration of the C-C bond. The origin of the selectivity observed from the two catalysts is discussed in relation to early and late transition states.     

Copper‐Catalyzed Formal [4+2] Cycloaddition of Enoldiazoimides with Sulfur Ylides

Enoldiazoimides, a new subclass of enoldiazo compounds, generate enol‐substituted carbonyl ylides whose reactions with sulfur ylides enable an unprecedented formal [4+2] cycloaddition. The resulting multifunctionalized indolizidinones, which incorporate sulfur, are formed in good yields under mild reaction conditions. The uniqueness of this transformation stems from the role of the silyl‐protected enol, since the corresponding acetyldiazoimide failed to provide any cross‐products in metal‐catalyzed reactions with sulfur ylides. This copper‐catalyzed cycloaddition is initiated with the generation of enol‐substituted carbonyl ylides and sulfur ylides from enoldiazoimides and sulfonium salts, respectively, and proceeds through stepwise six‐membered ring formation, C?O and C?S bond cleavage, and silyl and acetyl group migration.     

Synthesis of bicyclo[3.2.1]octanes by a tandem Diels-Alder-carbocation cyclization strategy

The bicyclo[3.2.1]octane ring system is assembled by a three-step process featuring a thermally induced [4+2] cycloaddition followed by a 1,3-benzodithiolium ion mediated cyclization onto an enol or silyl enol ether double bond.     

Pd-catalyzed decarboxylative arylation of silyl enol ester sp3 β-C-H bond under aerobic conditions

Pd-catalyzed aerobic oxidative coupling of various benzoic acids with silyl enol esters proceeds via a combination of decarboxylation with sp(3) β-C-H bond activation to give Heck-type products. Mechanistic studies reveal this coupling involves in situ generation of olefin from aerobic oxidation of silyl enolate, followed by decarboxylative Heck coupling.     

Amidyl Radical Directed γ-C(sp3)−H Functionalization with Silyl Enol Ethers via Photoredox Catalysis

Herein we reported an efficient photoredox-catalyzed reaction for site-selective C(sp³)−H functionalization of carboxamides with silyl enol ethers as radical acceptors. The reaction proceeded through amidyl radical-directed 1,5-hydrogen atom transfer (1,5-HAT) and C(sp³)−C(sp³) bond formation via radical addition of silyl enol ethers. The process features mild conditions and high functional-group tolerance, allowing the preparation of a series of carboxamides with pendant carbonyl moieties.     

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.     

Direct and indirect electrochemical generation of alkoxycarbenium ion pools from thioacetals

Thioacetals were found to be effective precursors to generate and accumulate alkoxycarbenium ions based on direct and indirect cation pool methods. Alkoxycarbenium ions thus generated reacted with carbon nucleophiles such as allylsilanes and enol silyl ethers to give C-C bond formation products in good yields.     

The crystallographic structure of a Lewis acid-assisted chiral Brønsted acid as an enantioselective protonation reagent for silyl enol ethers

It is difficult to control the enantioselectivity in the protonation of silyl enol ethers with simple chiral Br?nsted acids, mainly due to bond flexibility between the proton and its chiral counterion, the orientational flexibility of the proton, and the fact that the proton sources available are limited to acidic compounds such as chiral carboxylic acids. To overcome these difficulties, we have developed a Lewis acid-assisted chiral Br?nsted acid (LBA) system. The coordination of Lewis acids with Br?nsted acids restricts the orientation of protons and increases their acidity. Optically active binaphthol (BINOL) derivative.SnCl4 complexes are very effective as enantioselective protonation reagents for silyl enol ethers. However, their exact structures have not yet been determined. We describe here optically active 1,2-diarylethane-1,2-diol derivative.SnCl4 as a new type of LBA for the enantioselective protonation as well as its crystallographic structure. A variety of optically active 1,2-diarylethane-1,2-diols could be readily prepared by asymmetric syn-dihydroxylation. This is a great advantage over BINOL for the flexible design of a new LBA. The most significant finding is that we were able to specify the conformational direction of the H-O bond of LBA, which has some asymmetric inductivity, by X-ray diffraction analysis. The stereochemical course in the enantioselective protonation of silyl enol ethers using LBA would be controlled by a linear OH/pi interaction with an initial step. The absolute stereopreference in enantioselective reactions using BINOL.SnCl4 can also be explained in terms of this uniformly mechanistic interpretation.     

Reaction of phIO·HBF4/silyl enol ether adduct with olefins as general approach to carbon—carbon bond formation in AdE reactions using hypervalent iodine reagents

A simple method for method for new carbon-carbon bond formation in Ad_E reactions using the PhIO·HBF₄ complex and silyl enol ethers has been developed.     

1,4‐Addition of Bis(iodozincio)methane to α,β‐Unsaturated Ketones: Chemical and Theoretical/Computational Studies

1,4‐Addition of bis(iodozincio)methane to simple α,β‐unsaturated ketones does not proceed well; the reaction is slightly endothermic according to DFT calculations. In the presence of chlorotrimethylsilane, the reaction proceeded efficiently to afford a silyl enol ether of β‐zinciomethyl ketone. The C? Zn bond of the silyl enol ether could be used in a cross‐coupling reaction to form another C? C bond in a one‐pot reaction. In contrast, 1,4‐addition of the dizinc reagent to enones carrying an acyloxy group proceeded very efficiently without any additive. In this case, the product was a 1,3‐diketone, which was generated in a novel tandem reaction. A theoretical/computational study indicates that the whole reaction pathway is exothermic, and that two zinc atoms of bis(iodozincio)methane accelerate each step cooperatively as effective Lewis acids.     

Oxidative C-C bond-forming reaction of electron-rich alkylbenzyl ether with trimethylvinyloxysilane

Treatment of an electron-rich benzyl ether with DDQ at ambient temperature followed by addition of a silyl enol ether undergoes a C-C bond-forming reaction to afford 3-alkoxy-3-phenyl-propionyl compound. This is a general reaction and works well with a variety of silyl enol ethers to give carbonyl products in yields ranging from 10 to 85%.     

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.     

A Chiral N,N′‐Dioxide–ZnII Complex Catalyzes the Enantioselective [2+2] Cycloaddition of Alkynones with Cyclic Enol Silyl Ethers

A highly efficient enantioselective [2+2] cycloaddition between alkynones and cyclic enol silyl ethers was developed by using a chiral N,N′‐dioxide‐zinc(II) complex as a catalyst. This method functions well for a variety of terminal alkynes as well as cyclic enol silyl ethers, with good to excellent enantioselectivity (up to 97 % ee). This is also the first successful example for the catalytic enantioselective [2+2] cycloaddition of internal alkynes with cyclic enol silyl ethers to give fully substituted cyclobutenes. Meanwhile, the desired cyclobutene product can easily be transformed into fused cyclobutane derivatives.     

Exploiting Transient Radical Cations as Brønsted Acids for Allylic C–H Heteroarylation of Enol Silyl Ethers

Intermediary radical cations, generated through single-electron oxidation of enol silyl ethers by excited Ir-based photocatalysts, can be exploited as Brønsted acids for the activation of heteroarylcyanides. This strategy enables the direct allylic C−H heteroarylation of enol silyl ethers under visible-light irradiation.     

Cross-coupling reactions of organosilicon compounds in the stereocontrolled synthesis of retinoids

This paper presents a full account of the use of Hiyama cross-coupling reactions in a highly convergent approach to retinoids in which the key step is construction of the central C10-C11 bond. Representatives of two families of oxygen-activated dienyl silanes (ethoxysilanes and silanols) and of all reported families of "safety-catch" silanols (siletanes, silyl hydrides, allyl-, benzyl-, aryl-, 2-pyridyl- and 2-thienylsilanes) were regio- and stereoselectively prepared and stereospecifically coupled to an appropriate electrophile by treatment with a palladium catalyst and a nucleophilic activator. Both all-trans and 11-cis-retinoids, and their chain-demethylated analogues, were obtained in good yields regardless of the geometry (E/Z) and of the steric congestion in each fragment. This comprehensive study conclusively establishes the Hiyama cross-coupling reaction, with its mild reaction conditions and stable, easily prepared, ecologically advantageous silicon-based coupling partners, as the most effective route to retinoids reported to date.