A tandem non-aldol aldol Mukaiyama aldol reaction

[reaction: see text] A new one-pot tandem aldol process is described in which a secondary epoxy silyl ether is converted into the 1,5-bis-silyloxy-3-alkanone in good yield. Thus, treatment of the epoxy silyl ether 8 with TBSOTf and base affords the silyl enol ether 9 via non-aldol aldol rearrangement and addition of benzaldehyde and TBSOTf gives the ketone 10 with 4:1 syn selectivity. The diastereoselectivity changes to an anti preference for most aldehydes. This anti selectivity overwhelms the normal Felkin-Ahn preference; namely, the 1,5-anti isomer predominates even when it is anti-Felkin-Ahn.     

Intramolecular cyclization of beta-amino and beta-ammonio radicals: a new synthetic route to the 1-azabicyclo

Treatment of 1-(2-phenylselenoethyl)-1,2,5,6-tetrahydropyridine (15) with tributyltin hydride affords only the product of reduction, demonstrating the reluctance of the 5-hexenyl radical 9 to undergo ring closure. When the nature of the radical is modified, either by introduction of an ester group at C4 or via its quaternary ammonium salt, cyclization occurs readily; while the radical 52 gives an excellent yield of 1-methyl-1-azoniabicyclo[3.2.1.]octyl bromide (55) uncontaminated with the product of reduction, the bicyclic product from 21 is accompanied by some reduced material. Production of the unwanted alkene can be eliminated in the latter by recourse to the quaternary ammonium ester 1-(2-bromoethyl)-4-carbethoxy-1-methyl-1,2,5,6-tetrahydropyridinium bromide (35) which, when exposed to tributyltin hydride, affords a 1:1 endo/exo mixture of 4-carbethoxy-1-methyl-1-azoniabicyclo[3.2.1]octyl bromide (37) exclusively. These results support the demonstration of the powerful polar effect of an ester function when attached to the double bond of a 5-hexenyl system, a property which can be exploited in the case of the radical 58. Treatment of the precursor, 1-(2-bromoethyl)-3-carbethoxy-1-methyl-3-pyrrolinium bromide (60), with tributyltin hydride generates 58 which is found to cyclize with high regioselectivity, affording a convenient high-yielding synthesis of the endo/exo isomers of 3-carbethoxy-1-methyl-1-azoniabicyclo[2.2.1]heptyl bromide 57. The isomeric bicyclo[2.2.1]heptyl ester 63 was not detected. These observations are in accordance with predictions based upon frontier molecular orbital considerations.     

Peroxycarbenium-mediated C-C bond formation: applications to the synthesis of hydroperoxides and peroxides

The Lewis acid-mediated reaction of alkene nucleophiles with peroxyacetals provides an effective route for the synthesis of homologated peroxides and hydroperoxides. In the presence of Lewis acids such as TiCl(4), SnCl(4), and trimethylsilyl triflate, peroxyacetals and peroxyketals undergo reaction with allyltrimethylsilane, silyl enol ethers, and silyl ketene acetals to afford homoallyl peroxides, 3-peroxyketones, and 3-peroxyalkanoates, respectively. Reactions of peroxyacetals are Lewis acid dependent; TiCl(4) promotes formation of ethers while SnCl(4) and trimethylsilyl triflate promote formation of peroxides. Lewis acid-promoted reactions of silylated hydroperoxyacetals furnish silylated hydroperoxides, which can be deprotected to homologated hydroperoxides. Hydroperoxyketals undergo Lewis acid-mediated allylation to furnish 1,2-dioxolanes via attack of hydroperoxide on the intermediate carbocation. Lewis acid-mediated cyclization of unsaturated peroxyacetals furnishes 1,2-dioxanes, 1,2-dioxepanes, and 1,2-dioxacanes through 6-endo/exo, 7-endo/endo, and 8-endo/endo pathways. The corresponding reactions involving 6-endo/endo and 5-endo/exo pathways were unsuccessful.     

Chiral Zinc(II)‐Catalyzed Enantioselective Tandem α‐Alkenyl Addition/Proton Shift Reaction of Silyl Enol Ethers with Ketimines

A new catalytic asymmetric tandem α‐alkenyl addition/proton shift reaction of silyl enol ethers with ketimines was serendipitously discovered in the presence of chiral N,N′‐dioxide/Zn^II complexes. The proton shift preferentially proceeded instead of a silyl shift after α‐alkenyl addition of silyl enol ether to the ketimine. A wide range of β‐amino silyl enol ethers were synthesized in high yields with good to excellent ee values. Control experiments suggest that the Mukaiyama–Mannich reaction and tandem α‐alkenyl addition/proton shift reaction are competitive reactions in the current catalytic system. The obtained β‐amino silyl enol ethers were easily transformed into β‐fluoroamines containing two vicinal tetrasubstituted carbon centers.     

Vinyl ketones to allenes: preparation of 1,3-dien-2-yl triflates and their application in Pd-catalyzed reactions with soft nucleophiles

[chemical reaction: see text]. A general route of converting alkenyl ketones to functionalized allenes was developed. Substituted 1,3-dien-2-yl triflates, which were prepared from the alkenyl ketones via silyl dienol ethers, were excellent substrates for the palladium-catalyzed reaction with soft nucleophiles giving the multisubstituted allenes in high yields. Comparison between the dienyl triflates and analogous bromodienes in the Pd-catalyzed reaction was studied as well.     

Gallium tribromide catalyzed coupling reaction of alkenyl ethers with ketene silyl acetals

A 'Ga'llant couple: The α-alkenylation of esters was accomplished by GaBr(3) -catalyzed coupling between alkenyl ethers and ketene silyl acetals. In this reaction system, various alkenyl ethers, including those with vinyl and substituted alkenyl groups, were applicable, and the scope of applicable ketene silyl acetals was sufficiently broad. The mechanism is also discussed.     

Preparation of proximal β-hydroxy silyl enol ethers from α,β-epoxyketones using silyllithium reagents

A new method for the stereoselective preparation of proximal β-hydroxy silyl enol ethers from α,β-epoxyketones using silyllithium reagents has been developed. The reaction is believed to proceed via Brook rearrangement assisted by opening of the adjacent epoxide. A number of α,β-epoxyketones were reacted with methyldiphenylsilyllithium to form the corresponding proximal β-hydroxy silyl enol ethers in good to excellent yield and excellent stereoselectivity.     

Diastereoselective additions of nucleophiles to alpha-acetoxy ethers using the alpha-(trimethylsilyl)benzyl auxiliary

We report the diastereoselective addition of a variety of nucleophiles to alpha-(trimethylsilyl)benzyl-substituted oxocarbenium ions. The oxocarbenium ions are generated from alpha-acetoxy ethers, which are easily prepared via reductive acetylation of esters. The alpha-(trimethylsilyl)benzyl auxiliary produces good to excellent facial selectivity with a variety of nucleophiles, including silyl enol ethers, silyl ketene acetals, allylsilanes, and crotylsilanes. The utility of this auxiliary is further demonstrated in a complex ketone aldol coupling reaction. [reaction: see text]     

Stereoselective preparation of 1-siloxy-1-alkenylcopper species by 1,2-Csp2-to-O silyl migration of acylsilanes

1-Siloxy-1-alkenylcopper species were generated by 1,2-Csp2-to-O silyl migration of the copper enolates of acyltriphenylsilanes. The alkenylcopper species reacted with methyl, benzyl, allylic, and tributylstannyl halides to give geometrically pure (Z)-enol silyl ethers. In the presence of Pd(0) catalyst, the cross-coupling of the alkenyl copper species with aryl and alkenyl iodides also proceeded to give the (Z)-enol silyl ethers with high stereoselectivity.     

Preparation of silyl enol ethers from acyloin derivatives using silyllithium reagents

A new method for the regioselective preparation of silyl enol ethers from acyloin derivatives using silyllithium reagents has been developed. Both dimethylphenyl- and methyldiphenylsilyllithium were found to be effective, the latter providing greater stereocontrol. The reaction is believed to proceed via Brook rearrangement assisted by expulsion of the adjacent leaving group. A number of acyclic acyloin derivatives were reacted to form the corresponding silyl enol ethers in good to excellent yield.     

Access to 2-alkyl chromanones via a conjugate addition approach

The introduction of alkyl substituents at C-2 of chromanones via conjugate addition of silyl enol ethers to a variety of chromenones is reported. In most cases racemic 2-alkyl chromanones were obtained in good yield in the presence of TMSOTf. The copper(II)-promoted conjugate addition of silyl enol ethers to chromenones was also carried out, albeit in low yields and no selectivity. Reliable syntheses of the chromenones via acylation of the corresponding β-diketo-compounds are also described.     

Diastereoselective Diels-Alder reactions of N-sulfonyl-1-aza-1,3-butadienes with optically active enol ethers: an asymmetric variant of the 1-azadiene Diels-Alder reaction

The first detailed study of a room-temperature asymmetric Diels-Alder reaction of N-sulfonyl-1-aza-1,3-butadienes is reported enlisting a series of 19 enol ethers bearing chiral auxiliaries, with many providing highly diastereoselective (endo and facial diastereoselection) reactions, largely the result of an exquisitely organized [4+2] cycloaddition transition state. Three new, readily accessible, and previously unexplored auxiliaries rationally emerged from the studies and provide remarkable selectivities (two of these give 49:1 endo:exo and 48:1 facial selectivity) that promise to be useful in systems beyond those detailed.     

Vinyl polymerization versus [1,3] O to C rearrangement in the ruthenium-catalyzed reactions of vinyl ethers with hydrosilanes

Two reactions, vinyl polymerization and [1,3] O to C rearrangement of vinyl ethers, are investigated in the ruthenium-catalyzed reaction with hydrosilanes. The reaction pathways are dependent on the substituents of the vinyl ether, in particular, those of the alkoxy group. Primary-, secondary-, and tertiary-alkyl vinyl ethers, ROCHCH₂, are polymerized with ease to give the corresponding polymer in good yields. When R is electron-donating benzyl groups, the reaction does not give the polyvinyl ether but results in [1,3] O to C rearrangement to give the corresponding aldehyde, RCH₂CHO in moderate to good yields. The rearrangement selectively proceeds when vinyl ethers having α-substituents are used as the starting materials to give the corresponding ketones in high yields. With catalytic amounts of hydrosilanes, the rearrangement gives ketones or aldehydes selectively. In sharp contrast, use of excess amounts of hydrosilanes leads to the rearrangement followed by reduction of the formed carbonyl group to give the corresponding silyl ethers in good yields. Nature of catalytically active species is discussed.     

alpha-Nitration of Ketones via Enol Silyl Ethers. Radical Cations as Reactive Intermediates in Thermal and Photochemical Processes

Highly colored (red) solutions of various enol silyl ethers and tetranitromethane (TNM) are readily bleached to afford good yields of alpha-nitro ketones in the dark at room temperature or below. Spectral analysis show the red colors to be associated with the intermolecular 1:1 electron donor-acceptor (EDA) complexes between the enol silyl ether and TNM. The formation of similar vividly colored EDA complexes with other electron acceptors (such as chloranil, tetracyanobenzene, tetracyanoquinodimethane, etc.) readily establish enol silyl ethers to be excellent electron donors. The deliberate irradiation of the diagnostic (red) charge-transfer absorption bands of the EDA complexes of enol silyl ethers and TNM at -40 degrees C affords directly the same alpha-nitro ketones, under conditions in which the thermal reaction is too slow to compete. A common pathway is discussed in which the electron transfer from the enol silyl ether (ESE) to TNM results in the radical ion triad [ESE(*)(+), NO(2)(*), C(NO(2))(3)(-)]. A subsequent fast homolytic coupling of the cation radical of the enol silyl ether with NO(2)(*)() leads to the alpha-nitro ketones. The use of time-resolved spectroscopy and the disparate behavior of the isomeric enol silyl ethers of alpha- and beta-tetralones as well as of 2-methylcyclohexanone strongly support cation radicals (ESE(*)(+)) as the critical intermediate in thermal and photoinduced electron-transfer as described in Schemes 1 and 2, respectively.     

Maleimide-dimethylfuran exo adducts: effective maleimide protection in the synthesis of oligonucleotide conjugates

The reaction of maleimide-containing compounds with 2,5-dimethylfuran gives a mixture of exo and endo isomers from which the exo cycloadduct can be easily isolated taking advantage of its stability in concentrated aqueous ammonia. Bifunctional compounds incorporating a dimethylfuran-protected maleimide (exo adduct) have been attached to resin-linked oligonucleotide chains. Removal of protecting groups masking oligonucleotide functionalities followed by retro-Diels-Alder maleimide deprotection affords maleimido-oligonucleotides suitable for conjugation, as assessed by their reaction with different thiols.     

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.     

Diastereoselective alkylation and reduction of β-alkoxyacylsilanes: stereoselective construction of three contiguous stereogenic centers

The nucleophilic addition reaction to acylsilanes, having stereogenic centers at the α and β positions, derived from the aldol reaction of dimethyl acetals and acylsilane silyl enol ethers gives the corresponding α-silylalcohols in high yields with excellent diastereoselectivity. The protiodesilylation of α-silylalcohols proceeds with complete retention of the configuration. In addition, the reduction of acylsilanes having stereogenic centers at the α and β positions affords the corresponding α-silylalcohols in good yields with high diastereoselectivity similarly to the nucleophilic addition. And the treatment of acylsilanes having a phenyl group on silicon atom with fluoride ion results in the formation of phenyl carbinol derivatives via migration of the phenyl group with high diastereoselectivity.     

Stereo- and regioselective formation of silyl enol ethers via oxidation of vinyl anions

Oxidation of E- and Z-vinyl lithiums with silyl peroxides 5 affords silyl enol ethers 3 in good to excellent yield with retention of configuration. This methodology represents a useful new procedure for the stereo- and regioselective synthesis of ketone enolates.     

Remarkable tris(trimethylsilyl)silyl group for diastereoselective [2 + 2] cyclizations

[reaction: see text] Diastereoselective [2 + 2] cyclizations of aldehyde- and ketone-derived silyl enol ethers with acrylates is described. The use of the tris(trimethylsilyl)silyl group allows for unprecedented reactivity, yields, and selectivity for these cyclizations. The presence of silicon-silicon bonds proved to be important for this transformation, where typical silyl groups (TBS and TIPS) failed to give any desired product. The bulky bis(2,6-diphenylphenoxide) aluminum triflimide catalyst was essential for high diastereoselectivity.     

Synthetic applications in radical/radical cationic cascade reactions

Oxidative photoinduced electron transfer (PET) reactions have been performed with various cyclic cyclopropyl(vinyl) silyl ethers bearing an olefinic or acetylenic side chain. The reactions result in bi- to tetracyclic ring systems via a fragmentation-radical/radical cationic addition reaction pathway with well defined ring juncture. The mode of cyclisation (endo/exo) can be partially controlled by addition of nucleophiles due to the suppression of radical cationic reaction pathways. Quantum chemical calculation of the cyclisation transition states underline the experimentally found selectivities. Additional mechanistic studies concerning the saturation step reveal that the final radical is saturated mostly by the solvent and traces of water in the solvent.