Facile synthesis of oxaspirobicyclic butenolides via a domino Michael addition/aldol reaction/γ-lactonization sequence

A three-component domino reaction approach between a primary amine, a dialkyl acetylenedicarboxylate, and 1,3-dimethylalloxan that affords novel oxaspirobicyclic γ-butenolidobarbiturate derivatives is reported. The reaction sequence consists of an initial Michael-addition of primary amines to dialkyl acetylenedicarboxylates, followed by aldol-like reaction with 1,3-dimethylalloxan, and then γ-lactonization to afford the products. This cascade reaction sequence represents a rapid and unprecedented route to the described biologically interesting molecules.     

A new approach to highly substituted cyclopentanoids from a concise formal synthesis of (+)-roseophilin

A convergent reaction sequence involving a reductive coupling and a chiral Br?nsted acid catalyzed Nazarov reaction is utilized in a concise formal synthesis of (+)-roseophilin (11 steps via longest linear sequence, 10.2% yield, 95% ee).     

A stereospecific pathway for the introduction of deuterium on the brassinosteroid skeleton by reductive dechlorination of chlorocarbonates

A new and efficient procedure for the preparation of brassinosteroids labeled with hydrogen isotopes was developed. A four-step reaction sequence started with the selective oxidation of a 2,3-diol group to an α-hydroxy ketone, which was converted stereospecifically into a chlorocarbonate by reaction with triphosgene. A subsequent Pd-catalyzed reductive dechlorination with deuterium gas yielded deuterium-labeled brassinosteroid 2,3-carbonates. The reaction sequence was completed by base-catalyzed hydrolysis of the cyclic carbonate.     

Tandem Diels-Alder/fragmentation approach to the synthesis of eleutherobin

[reaction: see text] A synthesis of 28, the carbon framework of the eleutherobin aglycone, is reported in a 15-step sequence from readily available starting materials. The tandem Diels-Alder reaction of 6 and 7 to produce 18, in which three new rings and six new stereocenters are formed, is a key step in the reaction sequence.     

A practical one-pot radical-ionic sequence for the preparation of epoxides: application to the synthesis of unnatural polyhydroxylated alkaloids

An efficient one-pot sequence for the preparation of epoxides from α-iodoesters or α-iodonitriles and allylic alcohols is described. This sequence is based on the use of iodine atom transfer reaction onto allylic alcohols followed by a ring closing epoxidation reaction of the halohydrin intermediates. The feasibility of this sequence is showcased in the synthesis of the perhydroaza-azulene, an unnatural analog of castanospermine.     

Preparation of phenyl-butyraldehydes using a base-catalyzed aromatization of dienones

Seven aldehydes were prepared using a five-step sequence synthesis. The synthetic strategy involved the use of a novel aromatization reaction of dienones. These key intermediates were prepared following a sequence involving BAR of substituted tetralones, ketones reduction, protection of alcohol, and bis-allylic oxidation. The key step of the route is an aromatization promoted by basic reaction conditions of dienones leading to substituted 4-phenyl butanals.     

Effects of Reaction Sequence on the Colloidal Polypyrrole Nanostructures and Conductivity

The relationship between nanoscaled morphology and macroscopic electrical conductivity of polypyrrole (PPy) nanostructures was qualitatively investigated. The PPy nanostructures were prepared via microemulsion polymerization using ionic surfactants. The morphology of PPy was influenced by both the type of ionic surfactants and reaction sequences; specifically, the PPy structures were highly influenced by the reaction sequence when anionic surfactant of SDS was used. By changing reaction sequence, a gel-like PPy was formed influencing on the macroscopic electrical conductivity. The results indicate that the macroscopic conductivity of PPy is affected by its nanoscaled structures as determined by the reaction conditions.     

Total synthesis of panepophenanthrin

[reaction: see text] The biomimetic synthesis of the racemic dimer panepophenanthrin was achieved in good yield employing a tandem reaction sequence.     

Concise synthesis of guanidine-containing heterocycles using the Biginelli reaction

Two general methods for the synthesis of 2-imino-5-carboxy-3,4-dihydropyrimidines were developed using the three-component Biginelli reaction. The first method utilizes pyrazole carboxamidine, a beta-ketoester, and an aldehyde in an initial Biginelli reaction. After Boc protection, these products undergo aminolysis and acidic deprotection to generate 2-imino-5-carboxy-3,4-dihydropyrimidines in a four-step sequence. The second method utilizes a triazone-protected guanidine, a beta-ketoester, and an aldehyde in a Biginelli reaction. Acidic cleavage of the triazone yields 2-imino-5-carboxy-3,4-dihydropyrimidines in a two-step sequence. We also describe the further elaboration of several of these products using a tethered Biginelli reaction to give triazaacenaphthalene structures similar to those found in crambescidin and batzelladine alkaloids.     

Double- and triple-cobalt catalysis in multicomponent reactions

The combination of different types of cobalt-catalyzed transformations in one-pot procedures is described. One of the key building blocks, a boron-functionalized isoprene derivative (boroprene), led to the realization of four-component reaction sequences comprising the cobalt-catalyzed Diels-Alder and a 1,4-hydrovinylation reaction. Eventually, a reaction sequence including a cobalt-catalyzed Diels-Alder reaction, a cobalt-catalyzed 1,4-hydrovinylation, an allylboration, and a cobalt-catalyzed Alder-ene reaction led to a five-component one-pot reaction sequence in which five carbon-carbon bonds were formed in excellent regio- and diastereoselectivity to generate complex products in good overall yields.     

Indole synthesis by controlled carbolithiation of o-aminostyrenes

An effective synthesis of the functionalized indole ring system has been developed from substituted o-aminostyrene starting material. Our methodology involves a novel cascade reaction sequence of alkyllithium addition to the styrene double bond and subsequent trapping of the intermediate organolithium with a suitable electrophile, followed by an in situ ring closure and dehydration to generate the indole ring. This new reaction sequence allows for the introduction of molecular diversity at all positions on the indole scaffold. The procedure was shown to be successful with a range of both C and N substituents on the o-aminostyrenes. The reaction sequence was tolerant to the reactivity range of alkyllithiums such as tert-, sec-, and n-butyllithium. The electrophiles used were DMF, which generated indole products with C-2 unsubstituted, and nitriles, which incorporated the nitrile substituent at C-2. The o-aminostyrene starting materials were generated by a Pd-catalyzed cross-coupling reaction of a vinyl boronic acid equivalent with the readily available substituted o-bromoanilines.     

One-pot synthesis of 5-(furo[3,4-b]chromenyl)-5-hydroxybarbiturates via a three-component cascade reaction

A three-component domino reaction between a 3-formylchromone, an isocyanide, and 1,3-dimethylalloxan which affords novel 5-(furo[3,4-b]chromenyl)-5-hydroxybarbiturate derivatives is reported. The reaction sequence consists of an initial [4+1] cycloaddition followed by an activated electrophilic heteroaromatic substitution on the furan ring to afford the products. This novel cascade reaction sequence represents an atom-economic route to biologically interesting molecules.     

The solid-phase Nicholas reaction: scope and limitations

Two libraries of alpha-substituted alkynes has been prepared on solid phase using a sequential Sonogashira/Nicholas reaction approach. The scope of nucleophiles in the Nicholas reaction on solid phase has been investigated, including carbon, oxygen, nitrogen, sulfur, fluoride, and hydride nucleophiles. The conditions for the reaction sequence have been optimized in terms of Lewis acid, catalyst for the Sonogashira step, temperature, reaction time, and decomplexation method, enabling the five-step sequence to be performed in 1 day.     

Conversion of Allylic Alcohols into Allylic Nitromethyl Compounds via a Palladium-Catalyzed Solvolysis: An Enantioselective Synthesis of an Advanced Carbocyclic Nucleoside Precursor(1)

A two-step reaction sequence to homoallylic nitro compounds from allylic alcohols is presented. Ethoxy carbonylation of the alcohols with ethyl chloroformate provides the corresponding allylic ethyl carbonates in high yields. Exposure of these substrates to catalytic palladium(0) in CH(3)NO(2) initiates a reaction sequence, ionization-decarboxylation-nitromethylation, that culminates with the formation of nitroalkenes. The regio- and stereochemical outcomes of the nitromethyl allylation reaction can be explained by the behavior of the transient pi-allylpalladium complexes. This methodology serves as a centerpiece for the synthesis of an important carbocyclic nucleoside intermediate.     

7-Azaindoles via carbolithiation of vinyl pyridines

The sequential reactions of a pyridine vinylation and alkene carbolithiation constitutes a new route to substituted 7-azaindoles. The methodology involves a reaction sequence of controlled carbolithiation of the vinyl double bond, subsequent trapping of the formal di-anion intermediate with a suitable electrophile, followed by an in situ ring closure and dehydration. The reaction sequence allows for aryl, heteroaryl, alkyl and keto substituents to be included at different positions around the heterocycle.     

Synthesis of bavachromanol from resorcinol via a tandem cationic cascade/EAS sequence

The natural chalcone bavachromanol has been prepared through a tandem reaction sequence that joins cationic cyclization of an epoxide to an adjacent MOM-acetal with electrophilic aromatic substitution by a presumed methoxymethylene cation. Only a single regioisomer of the tandem product was observed, with substitution taking place exclusively ortho to the position of the original acetal. This regiocontrol provided a key intermediate from a symmetrical precursor, and allowed preparation of the meroterpenoid through a short reaction sequence.     

A strategy for the total synthesis of dragmacidin E. Construction of the core ring system

[reaction: see text] The construction of the dragmacidin core ring system by a route that features the application of a new indole annelation reaction sequence is described.     

Understanding the fate of the oxyallyl cation following Nazarov electrocyclization: sequential Wagner-Meerwein migrations and the synthesis of spirocyclic cyclopentenones

A general reaction sequence is described that involves Nazarov cyclization followed by two sequential Wagner-Meerwein migrations, to afford spirocyclic compounds from divinyl ketones in the presence of 1 equiv of copper(II) complexes. A detailed investigation of this sequence is described including a study of substrate scope and limitations. It was found that after 4π electrocyclization, two different pathways are available to the oxyallyl cation intermediate: elimination of a proton can give the usual Nazarov cycloadduct, or ring contraction can give an alternative tertiary carbocation. After ring contraction, either [1,2]-hydride or carbon migration can occur, depending upon the substitution pattern of the substrate, to furnish spirocyclic products. The rearrangement pathway is favored over the elimination pathway when catalyst loading is high and the copper(II) counterion is noncoordinating. Several ligands were found to be effective for the reaction. Thus, the reaction sequence can be controlled by judicious choice of reaction conditions to allow selective generation of richly functionalized spirocycles. The three steps of the sequence are stereospecific: electrocyclization followed by two [1,2]-suprafacial Wagner-Meerwein shifts, the ring contraction and then a hydride, alkenyl, or aryl shift. The method allows stereospecific installation of adjacent stereocenters or adjacent quaternary centers arrayed around a cyclopentenone ring.     

Conjugate addition-initiated Nazarov cyclization

A reaction sequence involving the 1,6-conjugate addition of a nucleophile to a dienyl diketone followed by Nazarov cyclization is described. Several nucleophiles are identified as competent initiators for the sequence. A different reaction outcome is observed when catalytic amounts of nucleophile are employed, involving elimination of the nucleophile after the electrocyclization.     

High‐Yielding Synthesis of the Anti‐Influenza Neuraminidase Inhibitor (−)‐Oseltamivir by Two “One‐Pot” Sequences

The efficient asymmetric total synthesis of (?)‐oseltamivir, an antiviral reagent, has been accomplished by using two “one‐pot” reaction sequences, with excellent overall yield (60 %) and only one required purification by column chromatography. The first one‐pot reaction sequence consists of a diphenylprolinol silyl ether mediated asymmetric Michael reaction, a domino Michael reaction/Horner–Wadsworth–Emmons reaction combined with retro‐aldol/Horner–Wadsworth–Emmons reaction and retro Michael reactions, a thiol Michael reaction, and a base‐catalyzed isomerization. Six reactions can be successfully conducted in the second one‐pot reaction sequence; these are deprotection of a tert‐butyl ester and its conversion into an acyl chloride then an acyl azide, Curtius rearrangement, amide formation, reduction of a nitro group into an amine, and a retro Michael reaction of a thiol moiety. A column‐free synthesis of (?)‐oseltamivir has also been established.