Methodology In Organic Synthesis Research Articles

Photochemical Route to the Synthesis of Thiolane 1-Oxides

The preparation of thiolane 1-oxide 10 by photochemically mediated rearrangement of sulfoxide 9 in high yield is described. The efficient construction of quaternary carbon centers underscores the utility of this methodology in organic synthesis. Further manipulation of photoadduct 10 leads to the formation of diverse heterocyclic structures.

Visible second-harmonic light generated from a self-organized centrosymmetric lattice of nanospheres

We designed and fabricated a centrosymmetric material where one may be able to consider an efficient quadratic nonlinear interaction. We followed a solid phase-supported organic synthesis methodology to covalently bind a large number of highly nonlinear molecules to the surface of polystyrene nanospheres. Such chemically modified optically nonlinear latex spheres, when suspended in water, are seen to perfectly self-organize into a centrosymmetric lattice. Taking advantage of the nonlinear interaction located at the sphere-water interface and the photonic crystal properties of the fabricated material we were able to generate second-harmonic light visible to the naked eye.

Kinetics of the Reaction between 2-Phenylpropionitrile and 2-Chloro-5-nitrotrifluoromethylbenzene under Phase-Transfer Catalysis

Phase-transfer catalysis (PTC) is a widely accepted methodology in organic synthesis. Although a great number of organic syntheses were reported in PTC conditions, systematic kinetic studies are scarce. In the present report, a detailed study of the kinetics of the reaction between 2-chloro-5-nitrotrifluoromethylbenzene (CNTFB) and 2-phenylpropionitrile anion (HPP-), under PTC, was performed under several conditions. The reaction was carried out either in toluene or chlorobenzene as the organic phase, in the presence of a concentrated aqueous solution of NaOH using tetraalkylammonium (Q+X-) salts as phase-transfer catalysts. The major product was 2-(4-nitro-2-trifluoromethylphenyl)-2-phenylpropionitrile, and its yield depends on the experimental conditions. Different aspects of the mechanism are discussed and quantified. Kinetic data were explained by means of an interfacial mechanism that involves the deprotonation of the adsorbed nucleophile precursor followed by its catalyst-mediated extraction to the organic phase. A multicomponent Langmuir-type interface was assumed. Although the extraction of OH- by catalyst to the organic phase is usually disregarded, the formation of the substrate hydrolysis product that leads to catalyst poisoning was also investigated. The influence of this side reaction on the yield of the main product was established. A discussion about the influence of this side process on the main reaction and the operating mechanism is presented.

치환된 Silylpropargylic Alcohol의 Ortho Ester Claisen 재배열반응의 입체 선택성에 관한 연구

The ortho ester Claisen rearrangement has been very useful synthetic methodology in organic synthesis. The ortho ester Claisen rearrangement of the propargylic alcohols has been very effective method for producing the corresponding allene esters of biologically significant. Particularly the rearrangement involving a β-substituted vinyl participant is a potentially powerful reaction because a diastereomeric allene product may be generated. However, only one example yielding 1,3-disubstituted allenes by ortho ester Claisen rearrangement has been examined using substituted secondary propynyl alcohols by Heathcocks group. His group was able to obtain high stereoselectivity (80-90% of the syn selectivity) of the rearrangement of the propynyl alcohol bearing a bulky alkyl group at C-1 position. The results are noteworthy due to the fact that the diastereoselectivity of the ortho ester Claisen rearrangement is generally moderate or poor because the mixture of E and Z of the vinyl moiety of the intermediate ketene acetal may be generated. 2c,4 The ortho ester Claisen rearrangement of substituted silylpropargylic alcohols might be an efficient route to obtain the stereo-defined substituted silylallenes which has been very useful intermediates in organic synthesis. Therefore, the study on the rearrangement of the 1-alkyl-3-silylpropynol 2 leading to the 1,3-disubstituted silylallenes 3 is reported in this paper.

The World of β‐ and γ‐Peptides Comprised of Homologated Proteinogenic Amino Acids and Other Components

The origins of our nearly ten-year research program of chemical and biological investigations into peptides based on homologated proteinogenic amino acids are described. The road from the biopolymer poly[ethyl (R)-3-hydroxybutanoate] to the beta-peptides was primarily a step from organic synthesis methodology (the preparation of enantiomerically pure compounds (EPCs)) to supramolecular chemistry (higher-order structures maintained through non-covalent interactions). The performing of biochemical and biological tests on the beta- and gamma-peptides, which differ from natural peptides/proteins by a single or two additional CH(2) groups per amino acid, then led into bioorganic chemistry and medicinal chemistry. The individual chapters of this review article begin with descriptions of work on beta-amino acids, beta-peptides, and polymers (Nylon-3) that dates back to the 1960s, even to the times of Emil Fischer, but did not yield insights into structures or biological properties. The numerous, often highly physiologically active, or even toxic, natural products containing beta- and gamma-amino acid moieties are then presented. Chapters on the preparation of homologated amino acids with proteinogenic side chains, their coupling to provide the corresponding peptides, both in solution (including thioligation) and on the solid phase, their isolation by preparative HPLC, and their characterization by mass spectrometry (HR-MS and MS sequencing) follow. After that, their structures, predominantly determined by NMR spectroscopy in methanolic solution, are described: helices, pleated sheets, and turns, together with stack-, crankshaft-, paddlewheel-, and staircase-like patterns. The presence of the additional C--C bonds in the backbones of the new peptides did not give rise to a chaotic increase in their secondary structures as many protein specialists might have expected: while there are indeed more structure types than are observed in the alpha-peptide realm - three different helices (10/12-, 12-, and 14-helix) if we include oligomers of trans-2-aminocyclopentanecarboxylic acid, for example - the structures are already observable with chains made up of only four components, and, having now undergone a learning process, we are able to construct them by design. The structures of the shorter beta-peptides can also be reliably determined by molecular-dynamics calculations (in solution; GROMOS program package). Unlike in the case of the natural helices, these compounds' folding into secondary structures is not cooperative. In beta- and gamma-peptides, it is possible to introduce heteroatom substituents (such as halogen or OH) onto the backbones or to incorporate heteroatoms (NH, O) directly into the chain, and, thanks to this, it has been possible to study effects unobservable in the world of the alpha-peptides. Tests with proteolytic enzymes of all types (from mammals, microorganisms, yeasts) and in vivo examination (mice, rats, insects, plants) showed beta- and gamma-peptides to be completely stable towards proteolysis and, as demonstrated for two beta-peptides, extraordinarily stable towards metabolism, even when bearing functionalized side chains (such as those of Thr, Tyr, Trp, Lys, or Arg). The beta-peptides so far examined also normally display no or only very weak cytotoxic, antiproliferative, antimicrobial, hemolytic, immunogenic, or inflammatory properties either in cell cultures or in vivo. Even biological degradation by microbial colonies of the types found in sewage-treatment plants or in soil is very slow. That there are indeed interactions of beta- and gamma-peptides with biological systems, however, can be seen in the following findings: i) organ-specific distribution takes place after intravenous (i.v.) administration in rats, ii) transport through the intestines of rodents has been observed, iii) beta-peptides with positively charged side chains (Arg and Lys) settle on cell surfaces, are able to enter into mammalian cells (fibroplasts, keratinocytes, HeLa cells), and migrate into their cell nuclei (and nucleoli), and iv) in one case, it has already been established that a beta-peptide derivative can up- and down-regulate gene expression rates. Besides these less sharply definable interactions, it has also been possible to construct beta- and gamma-peptide agonists of naturally occurring peptide hormones, MHC-binding beta-peptides, or amphipathic beta-peptide inhibitors of membrane-bound proteins in a controlled fashion. Examples include somatostatin mimics and the suppression of cholesterol transport through the intestinal brush-border membrane (by the SR-BI-protein). The results so far obtained from investigations into peptides made up of homologues of the proteinogenic amino acids also represent a contribution to deepening of our knowledge of the natural peptides/proteins, while potential for biomedicinal application of this new class of substances has also been suggested.

Evaluation of 17α- E-(trifluoromethylphenyl)vinyl estradiols as novel estrogen receptor ligands

As part of our program to develop novel ligands for the estrogen receptor, we synthesized the series of isomeric 17α-(trifluoromethyl)phenylvinyl estradiols using our solid-phase organic synthesis methodology. The compounds were evaluated for their relative binding affinity (RBA) using the ERα–LBD and in vivo potency using the immature rat uterotrophic growth assay. The ortho-isomer had the highest RBA values, 48–223, and the highest estrogenicity in vivo. The other isomers had significantly lower affinities and were weaker agonists in the uterotrophic assay. The results suggest that introduction of substituents at the 17α-position of estradiol is tolerated by the ER-LBD and permit agonist responses in the intact animal, however, the effect is sensitive to the position of groups on the phenyl ring. This study demonstrates that the 17α-position of estradiol is a reasonable site for modification but the position and physicochemical properties of such modifications may significantly affect the affinity and efficacy of the ligand.

Modular evolution of a chiral auxiliary for the 1,3-dipolar cycloaddition of isomünchnones with vinyl ethers.

[reaction: see text]. The 1,3-dipolar cycloaddition reaction has long been recognized as a powerful methodology in organic synthesis. More recently, this reaction has become a popular manifold for the construction of chemical diversity. Herein, we report the development of a chiral template for the facially selective cycloaddition of isomünchnones, a common class of 1,3-dipoles. The modular format of the asymmetric unit allowed a systematic optimization of selectivity. In addition, the chiral auxiliary was removed through an unusually facile ester aminolysis.

A síntese orgânica em fase sólida e seus suportes poliméricos mais empregados

In the last decade we have seen improved a powerfull tool to medicinal chemistry: the Solid Phase Organic Synthesis (SPOS). This metodology can be used to synthesize a large library of compounds in a short time by combinatorial chemistry, where simple chemical substances can be combinated one to each other building a library of complex compounds. In this work we present the solid phase organic synthesis and their advantage upon the tradicional organic synthesis methodology, as well as the main polimers used in the SPOS technique.

Organic Synthesis Methodology. Preparation and Diastereoselective Birch Reduction—Alkylation of 3‐Substituted 2‐Methyl‐2,3‐dihydroisoindol‐1‐ones.

AbstractFor Abstract see ChemInform Abstract in Full Text.

ChemInform Abstract: Phase‐Transfer Catalysis: A General Green Methodology in Organic Synthesis

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Organic synthesis methodology. Preparation and diastereoselective birch reduction-alkylation of 3-substituted 2-methyl-2,3-dihydroisoindol-1-ones.

Organic synthesis methodology. Preparation and diastereoselective birch reduction-alkylation of 3-substituted 2-methyl-2,3-dihydroisoindol-1-ones.

Phase-transfer catalysis. A general green methodology in organic synthesis

Abstract Basic concept of phase-transfer catalysis (PTC), its field of applications and specific features as the most general, efficient, and environment-friendly green methodology of organic synthesis, particularly for industrial processes, is discussed.

Sharpless Asymmetric Aminohydroxylation: Scope, Limitations, and Use in Synthesis.

As a valuable methodology for organic synthesis, asymmetric aminohydroxylation (AA)-the catalytic and asymmetric conversion of alkenes into enantiomerically enriched N-protected amino alcohols-has become established in a remarkably short period of time. Examples of the types of products that can be synthesized easily on a reasonably large scale and in enantiomerically pure form are shown in the picture.

Mannich reactions of resin-bound substrates: 2. A versatile three-component solid-phase organic synthesis methodology

Alkynes, secondary amines and aldehydes, in the presence of a copper (I) salt, undergo Mannich reactions to afford the corresponding aminomethylalkynyl adducts on a solid support. Any member of this three-component reaction system can be immobilized on a resin providing three distinct routes for the generation of structurally diverse compound libraries.

Protonation at the Aromatic Ring of Samarium Benzophenone Dianion Species. Isolation and Structural Characterization of a Samarium(III) Enolate Complex

The reduction of aromatic compounds into their dihydro derivatives by dissolving metal/alcohol systems (the Birch reduction) is a useful methodology in organic synthesis. Of particular importance is the reduction of aromatic carbonyl compounds such as aromatic acids, esters, amides, and monoaryl ketones, which usually generates in situ useful metal enolate intermediates that upon further reaction with electrophiles yield a variety of cyclohexadiene derivatives. One of the possible processes to generate these metal enolate intermediates is thought to be the monoprotonation of dianionic species at the para position of the aromatic rings. On the other hand, the reduction of diaryl ketones by alkali metals in liquid ammonia or by lanthanide metals in THF/HMPA or DME has been well known to afford the corresponding ketone dianions. The first X-ray structure of metal ketone dianion complexes, [Yb([mu]-[eta][sup 1],[eta][sup 2]-OCPh[sub 2]) (HMPA)[sub 2]][sub 2], has been recently determined in this laboratory. Protonation of this complex with ArOH or CpMo(CO)[sub 3]H also occurred at the carbonyl unit to release benzhydrol. In striking contrast to these results, when the analogous samarium benzophenone dianion species was aallowed to react with ArOH, the protonation occurred at the aromatic ring to give a samarium(III) enolate complex. 15 refs., 1more » fig.« less

An organosilicon route to the B-norbenzomorphan skeleton

Organosilicon compounds are receiving increased attention on account of their interesting chemical properties, which have resulted in synthetic applications.’ Organosilicon chemistry has therefore become important in the methodology of organic synthesis. Despite evident POtential applications of benzofuaed sixand seven-membered heterocycles in medicinal chemistry,* only limited results are available on the silylation of heterocyclic compounds. Of particular interest in this regard is the case of quinoline derivatives that could lead to new organosilicon synthon development. The only literature in this area concerns the silylation of quinoline itself.a4 We previously showed4 that it is possible to increase yields of silylated products and modify the course of the reaction by varying the experimental conditions. We report now results on quinaldine using two silylation reagents: Me3SiCl/Li/THF and MesSiCl/ Mg/THF. The influence of the metal upon the regioand stereochemistry of silylation is probed; the chemical behavior of the N-silylated products is investigated and interpreted by quantum mechanics calculations.

Development of Newer Methodologies in Organic Synthesis

Development of Newer Methodologies in Organic Synthesis

ChemInform Abstract: Stereoselective Isomerization of Acetylenic Derivatives as a New Methodology in Organic Synthesis

The transition metal catalyzed isdmerization reac- tions of acetylenic derivatives were studied. (E,E)-Conju- gated dienones, dienoic esters and dienoic amides were syn- thesized from corresponding a,b-ynones, 2-ynoic esters and 2-ynoic amides, respectively. 2-Ynols were first isomerized to the corresponding 2-enones or 2-enals. The reactions can be accomplished simply, in high yield, and stereoselectively. It is proposed that allenic compounds are initially formed as the main intermediates and then isomerized further to the products. A convenient and potential useful methodology is provided for the preparation of important intermediates in the synthesis of natural products.

Stereoselective isomerization of acetylenic derivatives as a new methodology in organic synthesis

Abstract

Concluding remarks

Organometallic chemistry is now firmly entrenched in the methodology of organic synthesis. That this is so has been clearly demonstrated during the course of this meeting. Two themes have emerged. First, the power of organometallic reagents to provide enhanced selectivity in stoichiometric processes. In this area the use of carbene complexes, transition metal acyls, 7t-allyIs and arenes are already offering powerful new methods for the synthesis of a wide range of functionalized compounds with very high diastereo- and enantioselectivities. Many of the methods described are already efficient and routine. Intramolecular cycloadditions of eneynes, catalysed by palladium, now represent short routes to polycyclic systems of some complexity. Even in the held of selective protection organometallics offer advantages, for example in the case of reactive acetylenes.