Sulphur in the Strategy of Natural Products Synthesis

Abstract

Syntheses of secondary metabolites of α-and β-mercapto aminoacids are described. The strategy in the first class of compounds consists of using N-hydroxy-α-amino acid derivatives as intermediates and of converting them into α-functionalized, in particular thiol-substituted amino acids; as examples serve syntheses in the gliotoxin and sporidesmin series. In the second class of compounds the cycloaddition products of indole derivatives, having sulfide substituents, and nitroso olefins are transformed into indole alkaloids, in particular tryptathionins, by rearrangement and further reactions. The antitumor agent sparsomycin has been synthesized via an amino sultine and its stereospecific nucleophilic ring opening. Bioassays done with this compound and sixteen of its structural analogs gave insight in the structural features that are required for sparsomycin's antitumor activity.     

Lewis acid-mediated rearrangement of activated cyclic amines: a facile synthetic protocol for the preparation of amino carbonyl compounds

Ring opening of activated cyclic amines to produce amino carbonyl compounds has been studied in the presence of Lewis acids. Whereas five- and six-membered rings cleave and rearrange via a 1,2-hydride shift, reaction in three- and four-membered rings takes place via a C-C bond migration. In the case of a three-membered ring, a wide variety of Lewis acids proved to be effective for the reaction. Base-induced ring opening of activated alpha,alpha-disubstituted azetidinemethanol and its mechanistic aspects have been studied.     

Diastereoselective Nucleophilic Ring‐Opening Reactions of 2,6‐Diazasemibullvalenes for the Synthesis of Diverse Functionalized Δ1‐Bipyrroline Derivatives

Nucleophilic ring‐opening reactions of 2,6‐diazasemibullvalenes (NSBVs) were investigated. Different types of nucleophile (alcohols, phenols, thiols, carboxylic acids, water, enols, amines, indoles, metal‐halide salts, sodium azide, organozinc compounds, lithium alkynethiolate, and sulfoxonium ylides) were used to afford diverse functionalized Δ¹‐bipyrroline derivatives in good yields with high regio‐ and diastereoselectivity. Most of the reactions featured milder conditions and higher reactivity relative to those for common aziridine derivatives, probably because of the rigid ring system and substitution patterns of NSBVs.     

Synthesis of chiral iodo-N,O-acetonide aminal scaffolds via an efficient cascade reaction of amino acid-derived epoxides

Novel amino acid-derived iodo-N,O-acetonide aminals were developed as chiral, non-epimerizable scaffolds to facilitate complex molecule synthesis. These scaffolds are readily prepared from commercially available amino acid derivatives in ?6 steps, contain an orthogonally-protected β-hydroxy amine moiety, and feature a directly reactive alkyl-iodide group for facile substitution chemistry. Further, a novel ring opening/cyclization cascade reaction was developed to prepare these compounds efficiently (59-72%) from readily available epoxide derivatives.     

Synthesis of Functionalized Novel α‐Amino‐β‐alkoxyphosphonates through Regioselective Ring Opening of Aziridine‐2‐phosphonates

Aziridines are highly useful compounds as building blocks for the synthesis of important organic compounds. Amino acid synthesis by aziridine ring opening reaction is a good example to the use of aziridines. Although this reaction is studied by many groups, the synthesis of amino phosphonic acids is less explored. In this study, we have carried out the ring opening reaction of aziridinyl phosphonates with a variety of alcohols including the more functional propargylic and allylic alcohols. These reactions provided functionalized α‐amino‐β‐alkoxyphosphonates in 40–91 % yield.     

SIMPLE ROUTE TO CYCLOPENTANOL DERIVATIVES

We described here an efficient and short new method to synthesize cyclopentanol derivatives. Ring opening of spiroepoxide 3 was done easily by an amine or ethyl carbamate leading to new molecules bifunctionalized. The characteristic ¹H and ¹³C NMR spectroscopic features of the synthesized compounds are reported.     

Selenium-Containing π-Conjugated Compounds for Electronic Molecular Materials

Abstract

Novel selenium-containing π-conjugated compounds have been studied for the development of organic metals, superconductors, and field-effect-transistors. Methylenedithiotetraselenafulvalene (MDT-TSF) and its related electron donors are effectively synthesized by the recently developed synthetic method consisting of the one-pot formation of 1,3-diselenole-2-selones, the deprotection/realkylation procedure of the protected tetrachalcogenafulvalene-thiolate and -selenolate, and the ring closing reaction via trans-alkylation on sulfur or selenium atom. These new compounds serve as good electron donors for developing not only highly conducting charge-transfer salts (> 10 ³ S cm^?1) but also superconducting salts. Among six selenium-containing methylenedichalcogeno-tetrachalcogenafulvalenes, we found that four of them can produce superconducting salts, indicating that the present compounds are superior class of electron donors.

For the development of high-performance organic semiconductors for organic field effect transistor (OFET) devices, we focused our attention to selenophene-containing acene-type compounds, namely benzo[1,2-b:4,5-b′]diselenophene (BDS) derivatives hitherto unknown. A new synthetic method for BDS derivatives consisting of double heterocycle-formation on the central benzene ring has been established and has made it possible to synthesize a range of BDS derivatives. Among them, 2,6-diphenyl derivative (DPh-BDS) shows very high hole mobility of 0.17 cm ² /Vs, which is classified into the highest class of field-effect mobility of organic thin films.     

Cyclopalladation and Reactivity of Amino Esters through C?H Bond Activation: Experimental,Kinetic, and Density Functional Theory Mechanistic Studies

The orthopalladation, through C? H bond activation, of a large number of amino esters and amino phosphonates derived from phenylglycine, and having different substituents at the aryl ring and the C‐α atom, as well as on the N‐amine atom, has been studied. The experimental observations indicated an improvement in the yields of the orthopalladated compounds when the N‐amine and/or the C‐α atom are substituted, when compared with the unsubstituted methyl phenylglycinate derivatives. In contrast, substitutions at the aryl ring do not promote significant changes in the orthometalation results. Furthermore, the use of hydrochloride salts of the amino esters has also been shown to have a remarkably favorable effect on the process. All these observations have been fully quantified at different temperatures and pressures by a detailed kinetic study in solution in different solvents and in the presence and absence of added Brønsted acids and chloride anions. The data collected indicate relevant changes in the process depending on these conditions, as expected from the general background known for cyclopalladation reactions. An electronic mechanism of the orthopalladation has been proposed based on DFT calculations at the B3LYP level, and a very good agreement between the trends kinetically measured and the theoretically calculated activation barriers has been obtained. The reactivity of the new orthopalladated amino phosphonate derivatives has been tested and it was found that their halogenation, alkoxylation and carbonylation resulted in formation of the corresponding functionalized ortho‐haloaminophosphonates, ortho‐alkoxyaminophosphonates and oxoisoindolinylphosphonates.     

A Precautionary Note Regarding Derivatization of Secondary Amines with Dialkylacetals of Formamide Other Than the Diethyl Derivative

Abstract

We have extended our earlier work on alkylation of secondary amino compounds with dimethylformamide diethyl acetal to other alkyl acetals, such as dimethyl and dipropyl acetal. All the alkylating DMT-dialkyl acetal reagents tested gave only N-ethyl derivatives of the secondary amines. The reagent purity was tested by preparing the esters of carboxylic acids, where the appropriate alkyl (methyl or propyl) ester is obtained. It is concluded that all dimethylformamide dialkyl acetals yield a single N-ethyl derivative of secondary amine. The reaction mechanism is not understood.     

Reaction of Amino Acid Esters and Amides with o-Phthalaldehyde. Limitations in Fluorescent Yield

Abstract

Amino acid esters and amides fail to produce strong fluorescence following their reaction with o-phthalaldehyde (OPA) in the presence of β-mercaptoethanol. The lack of luminescence appears to arise from a quenching phenomenon rather than from reduced reactivity of these substrates toward OPA. The amido hydrogen in the peptide linkage has been implicated in the loss in fluorescence yield.

o-Phthalaldehyde (OPA) has proven to be a very useful reagent for converting amino acids to fluorescent isoindole derivatives¹. This derivatization process permits the visualization of femtomolar quantities of amino acids. Unfortunately, this technique has not been applied successfully to the derivatization of peptides^2,3, except for those containing lysine residues, in which the terminal amino group is attacked by the reagent⁴. It is the purpose of this note to more clearly define the limitations of OPA as a fluorogenic reagents for peptides and amino acid esters.     

Ring–Opening of a Carbohydrate Triflate to form an Acyclic Alkene

ABSTRACT

The ease with which carbohydrate trifluoromethanesulfonates (triflates) undergo substitution reactions with a wide variety of nucleophiles¹ has allowed these compounds to play an increasingly important role in synthetic carbohydrate chemistry.² The exceptional reactivity of triflates also creates an opportunity for unusual reactions to occur;³ for example, triflyl group migration⁴ and internal displacement by very weak nucleophiles⁵ both have been observed. Also, carbohydrate triflates have been used as alkylating agents in oligosaccharide synthesis.⁶ In this communication a new triflate reaction is described. This new process is one in which departure of the triflyloxy group is accompanied by ring opening to give an acyclic alkene.     

Novel,environmentally friendly crosslinking system of an epoxy using an amino acid: Tryptophan‐cured diglycidyl ether of bisphenol A epoxy

Tryptophan, an amino acid, has been used as a novel, environmentally friendly curing agent instead of toxic curing agents to crosslink the diglycidyl ether of bisphenol A (DGEBA) epoxy resin. The curing reaction of tryptophan/DGEBA mixtures of different ratios and the effect of the imidazole catalyst on the reaction have been evaluated. The optimum reaction ratio of DGEBA to tryptophan has been determined to be 3:1 with 1 wt % catalyst, and the curing mechanism of the novel reaction system has been studied and elucidated. In situ Fourier transform infrared spectra indicate that with the extraction of a hydrogen from NH₃⁺ in zwitterions from tryptophan, the formed nucleophilic primary amine and carboxylate anions of the tryptophan can readily participate in the ring‐opening reaction with epoxy. The secondary amine, formed from the primary amine, can further participate in the ring‐opening reaction with epoxy and form the crosslinked network. The crosslinked structure exhibits a reasonably high glass‐transition temperature and thermal stability. A catalyst‐initiated chain reaction mechanism is proposed for the curing reaction of the epoxy with zwitterion amino acid hardeners. The replacement of toxic curing agents with this novel, environmentally friendly curing agent is an important step toward a next‐generation green electronics industry. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 181–190, 2007     

One-pot synthesis of 4,5-dihydro-1H-pyrrol-3-carboxamide derivatives via a four-component reaction

An effective route to functionalized 4,5-dihydro-1H-pyrrol-3-carboxamide derivatives is described. This involves reaction of N-alkyl-3-oxobutanamides, which result from the addition of an amine to the diketene, and a primary amine in the presence of dibenzoylacetylene. The 1,3-dicarbonyl compounds obtained from the addition of an amine to diketene were trapped with a primary amine to produce (Z)-3-(alkylamino)-N¹-alkyl-2-butenamide, which reacts with dibenzoylacetylene to produce 4,5-dihydro-1H-pyrrol-3-carboxamide derivatives.     

N-Vinylformamide – Building Block for Novel Polymer Structures

Abstract

N-Vinylformamide (NVF, N-ethenylformamide) is a precursor to amide and amine functional polymers and to other monomers, oligomers, and functional polymers. NVF shows attractive physical and toxicological properties and high reactivity, both in polymerization and in subsequent hydrolysis to cationic and reactive amine functional polymers or oligomers. NVF radical polymerization readily yields water soluble homopolymers with molecular weights from 10⁴ to >10⁶. Copolymerizability is similar to other vinyl amides. Unexpectedly, NVF will also undergo cationic oligomerization. Hydrolysis of polymers and copolymers with base or acid is facile, although reactions with neighboring groups (e.g., with coacrylate ester groups to give lactams) complicate copolymer hydrolysis.

Reaction of NVF at the unusually acidic NH group allows reaction with isocyanates to give vinylacylureas or Michael addition to acrylates to give a family of new N-vinylformamidopropionate esters. These esters in turn react with functional amines to generate new families of divinyl, vinyl/alcohol functional, or vinyl/amino functional comonomers. Applications for NVF and its derived monomers and polymers appear numerous, in particular in radiation cure coatings, based on their good physical and toxicological properties.     

The Direct Electrochemical Detection of Amino Acids at a Platinum Electrode in an Alkaline Chromatographic Effluent

Abstract

It is the general experience that most organic compounds including amino acids do not produce reversible or even quasi-reversible anodic waves at a Pt electrode under conditions of conventional cyclic voltammetry. Furthermore, amperometric detection of these compounds at a constant electrode potential is not successful because of the accumulation of adsorbed reaction products and/or an oxide film at the electrode surface. However, it is observed that a Pt electrode surface is cleaned quite effectively of adsorbed organic molecles and radicals simultanaeously with the anodic formation of the oxide layer. This oxidation of adsorbed organic species is concluded to be electrocatalyzed by PtOH formed as the first step in the production of the oxide layer (PtO). A pulsed-potential waveform applied at a frequency of ca. 1 Hz is demonstrated to provide direct amperometric detection of adsorbed amino acids at a Pt electrode. Satisfactory analytical precision (i.e., < 3% rel. std. dev.) results because the waveform reproducibly generates the catalytically active surface state at the Pt electrode. Both primary and secondary amino acids are determined with satisfactory detection limits: e.g., ca. 13 ng for glycine, 7 ng for phenylamine and 23 ng for hydroxyproline in 50-μL samples. Analytical response is concluded to depend on the adsorption isotherm of the amino acid being detected. Hence, the calibration plot of I/I_peak vs. 1/C^D is linear for low surface coverages. Results are shown for amperometric detection of a synthetic mixture of amino acids by anion-exchange chromatography using NaOH as the eluent and supporting electrolyte.     

Chemiluminescence Detection of Amino Acids,Peptides, and Proteins Using Tris-2,2′-Bipyridine Ruthenium (III)

Abstract

The feasibility of using the tris-2-2′-bipyridine ruthenium (III) (Ru(bpy)₃ ^{3 +}) chemiluminescent (CL) reaction for the detection of amino acids, peptides, and proteins has been studied.

Detection limits of the amino acids as determined by flow injection analysis (FIA) ranged from 20 pmol of proline to 50 nmol of asparagine. In general, amino acids containing secondary amine groups yielded the strongest responses. A reaction mechanism for Ru (bpy)₃ ^{3 +} chemiluminescence of aliphatic amines has been proposed. Studies of peptide molecules and poly-prolines showed that the peptide bond barely contributes to the detection signals. The separation of hydroxyproline and proline in synthetic collagen by HPLC with Ru (bpy)₃ ^{3 +} chemiluminescence detection has been shown to be possible.     

Radioprotective and Antitumor Activity of Some Novel Amino Acids and Imidazoles Containing Thieno[2,3-d]pyrimidine Moiety

A variety of novel thieno[2,3-d]pyrimidine derivatives, comprising amino acids 3a–l, imidazothieno-pyrimidines 4A, 4b–h, and 7, were obtained via the reaction of 4-chloro-5,6-dimethylthieno[2,3-d]pyrimidine 1 with a variety of reagents. The structures of these compounds were confirmed by microanalysis, IR, ¹H NMR, and mass spectrometry. Some of the obtained compounds showed promising radioprotective and antitumor activities.     

Synthesis and mechanism of formation of novel 2,5-dihydro-2,5-diimino-3,4-di[(N,N-dimethylamino)methylideneamino]pyrroles and 5-amino-3,4-di[(N,N-dimethylamino)methylideneamino]-2H-2-iminopyrroles

Formation of 5-amino-3,4-di[(N,N-dimethylarnino)methylidenearnino]-2H-2-iminopyrroles 3 from the reaction of (Z)-N¹-(2-amino-1,2-dicyanovinyl)-N²-substituted-formamidines 1 with dimethylformamide diethyl acetal has been shown to occur by initial formation of (Z)-N¹-{l,2-dicyano-2-[N,N-dimethylamino)methylideneamino]vinyl}formamidines 8 (isolated), followed by base catalysed cyclisation and imi dazole ring opening by dimethyl amine. The kinetic product of the ring opening reaction is the 2,5-diimino2,5-dihydropyrrole derivatives 11, which have been isolated and characterized spectroscopically and by a single crystal X-ray analysis on the R = Ph derivative. In solution at room temperature the N-aryl derivatives undergo a rapid Dimroth rearrangement to give the thermodynamic ally more stable isomer 3 , but compound 11 (R = Me) is much more stable in solution.     

新型多重氮杂杯[4]芳烃衍生物的合成

对叔丁基杯[4]芳烃-1,3-二醛基衍生物1与水杨酰肼、烟酰肼、异烟酰肼反应, 合成了具有开链结构新型杯[4]多重氮杂衍生物2a～2c, 产率分别为88%, 85%和90%. 化合物1与乙二酰肼、丙二酰肼、己二酰肼反应, 得到具有桥联结构的新型杯[4]多重氮杂衍生物3a～3c, 产率分别为86%, 89%和90%. 新化合物的结构经元素分析、质谱、核磁共振谱等表征证实, 杯[4]芳烃单元均为1,3-取代且采取锥式构象.     

Structure/reactivity/photoinitiation ability relationships in novel benzo pyrazolo (or imidazo) isoquinolinone derivatives upon visible light LEDs

Isoquinolinone derivatives bearing amino‐ or nitro‐ substituent (IQNs) have been synthesized as photoinitiators and combined with various additives (i.e., iodonium salt, N‐vinylcarbazole, amine or 2,4,6‐tris(trichloromethyl)?1,3,5‐triazine) to initiate ring‐opening cationic polymerizations (CP) or free radical polymerizations under exposure to visible LEDs (e.g., LEDs at 405 nm or 455 nm, or cold white LED) or a halogen lamp. Compared to the well‐known camphorquinone‐based systems, the novel IQNs‐based combinations employed here demonstrate higher efficiencies for the CP of epoxides. The photochemically generated reactive species (i.e., cations and radicals) from the IQNs‐based systems have been investigated by steady state photolysis, cyclic voltammetry, fluorescence, laser flash photolysis, and electron spin resonance spin trapping techniques. The structure/reactivity/photoinitiating ability relationships of IQNs‐based combinations are also discussed; the crucial role of the excited state lifetimes of the photoinitiators to ensure efficient quenching by additives is clearly underlined. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 1806–1815