Improved synthesis of structural analogues of (−)-epicatechin gallate for modulation of staphylococcal β-lactam resistance

The high-yielding synthesis of enantiomerically pure epicatechin gallate analogues where the A and/or B-ring hydroxylation is reduced or altered has been achieved by optimising routes to the catechin stereochemistry. The B-ring analogues were synthesised by using an electrophilic ring closure onto an enantiomerically enriched epoxide as a key step. The A and B-ring hydroxyl-deleted analogues were synthesised through a Mitsunobu cyclisation. For the B-ring analogues, the anti- (catechin) stereochemistry was converted to the syn- (epicatechin) stereochemistry by a known oxidation/reduction protocol. Absolute stereochemistry was derived from either a Sharpless epoxidation or asymmetric dihydroxylation.     

Titanium-mediated reductive cross-coupling reactions of imines with nitriles: an efficient route for the synthesis of α-aminoketones or 1,2-diketones

The reaction of imines with low-valent titanium species, generated in situ by using Ti(OⁱPr)₄/2 c-C₅H₉MgCl reagent, affords titanium–imine complex, which can couple with nitriles to provide 2,5-diazatitanacyclopentenes. α-Aminoketones are obtained in good yields by quenching the corresponding 2,5-diazatitanacyclopentenes with aqueous HCl solution. However, when the reaction is first quenched with MeOH in air followed by addition of aqueous HCl solution, 1,2-diketones are formed in good to high yields.     

Synthesis of C-glycoside analogues of α-galactosylceramide via linear allylic C-H oxidation and allyl cyanate to isocyanate rearrangement

C-Glycoside analogues of α-galactosylceramide were synthesized in which several significant modifications known to promote Th-1 cytokine production were included. The key transformations include C-H oxidation, Sharpless asymmetric epoxidation, olefin cross metathesis, and an allyl cyanate to isocyanate rearrangement.     

Transannular Claisen rearrangement reactions for the synthesis of vinylcyclobutanes: formal synthesis of (±)-grandisol

Unsaturated eight-membered lactones undergo decarboxylative and non-decarboxylative transannular Ireland-Claisen rearrangement reactions, to give substituted vinylcyclobutanes. A formal synthesis of (±)-grandisol is described.     

Improved synthesis of α-Methylene-γ-lactones via organotin reagents

The products of the reaction between aldehydes and the organotin reagent (1) have been converted to the corresponding α-methylene-γ-lactones in excellent yield under extremely mild conditions.     

Diphenylparabanic acid as a synthon for the synthesis of α-diketones and α-ketocarboxylic acids

Diphenylparabanic acid was found to react with >2 equiv of organolithiums at -78 °C to effectively give the corresponding symmetrical α-diketones. However, upon treatment with 1 equiv of organolithium, the parabanic acid gave mainly 5-substituted 5-hydroxyimidazolidine-2,4-diones. On the other hand, Grignard reagents were less reactive toward the parabanic acid at low temperature, and selectively gave the corresponding 5-hydroxyimidazolidine-2,4-diones even if more than 1 equiv of the reagents was used. A tandem process in which the parabanic acid was first reacted with a Grignard reagent and then reacted in one-pot with an organolithium effectively gave the unsymmetrical α-diketone. 5-Substituted 5-hydroxyimidazolidine-2,4-diones were useful as versatile precursors for preparing α-ketocarboxylic acids as well as unsymmetrical α-diketones.     

Enantioselective synthesis of gabapentin analogues via organocatalytic asymmetric Michael addition of α-branched aldehydes to β-nitroacrylates

Michael addition reaction of α-branched aldehydes to β-nitroacrylates was successfully carried out by using a mixed catalyst consisting of a primary amino acid, L-phenylalanine, and its lithium salt to give β-formyl-β'-nitroesters having a quaternary carbon centre in good yields (up to 85%) with high enantioselectivity (up to 98% ee). By using benzyl β-nitroacrylates as Michael acceptors, the obtained β-formyl-β'-nitroesters were converted into various 4,4-disubstituted pyrrolidine-3-carboxylic acids including analogues of gabapentin (Neurotin(?)) in one step from the Michael adducts in high yields.     

One-pot synthesis of trans-β-lactams from ferrocenylketene generated by thermal Wolff rearrangement

A series of β-lactams containing the ferrocene moiety were synthesized through the Staudinger reaction between ferrocenylketene generated by the thermal Wolff rearrangement of the corresponding diazo ketone and various imines. The stereochemical outcome has been investigated and the trans-products were isolated as the main products, opposite to the reported results by Bonini and coworkers. The absolute configuration of (±)-trans-1,4-diphenyl-3-ferrocenylazetidin-2-one (3c) was determined by X-ray analysis. The stereoselectivity is discussed from the viewpoint of the reaction mechanism.     

Camphor-based oxazaphospholanes as chiral templates for the enantioselective synthesis of α-chlorophosphonic acids

Constrained camphor-derived oxazaphospholanes have provided an efficient entry for the preparation of enantiomerically enriched α-chlorophosphonic acids.     

Correction to: New crystal structures of fluorinated α-aminophosphonic acid analogues of phenylglycine

Structural Chemistry - Corrections are needed to the original version of this article.     

Total synthesis of (±)-fumimycin and analogues for biological evaluation as peptide deformylase inhibitors

A concise 7-step total synthesis of (±)-fumimycin in 11.6% overall yield is reported. An acid-catalyzed intramolecular aza-Friedel–Crafts cyclization was developed to construct the benzofuranone skeleton of the natural product bearing an α,α-disubstituted amino acid moiety in a single step. Regioselective chlorination followed by a Suzuki–Miyaura cross-coupling rapidly enabled the preparation of a library of analogues which were evaluated against peptide deformylase for antibacterial activity.     

Pattern recognition methods in the study of thermal decomposition of α-amino acids

There are many examples in the literature of a strict relation between the pathways of decomposition of a drug substance and chemical structure of its molecule. For this reason, a study has now been performed on the relation between thermal decomposition of ??-amino acids and their chemical structure. To achieve this goal, a group of a dozen or so compounds was chosen at random, and the results obtained using the DTA, TG and DTG analyses of their thermal decomposition were interpreted by highly advanced multivariate methods, principal component analysis and cluster analysis. By this statistical analysis, the influence of specific functional groups on thermal decomposition of ??-amino acids was determined. It has been found that first two principal components explain together more than 75?% of variance, and in an exceptional case, about 90?%. The third stage of decomposition was that at which the thermoanalytical data were best correlated with chemical constitution of a compound. It has also been recognized that a better discrimination among the analysed compounds was obtained for the DTA data set. The results can be useful for identification of a relation between the pathway of degradation of a drug substance and chemical structure of its molecule, and for predicting chemical stability of the compounds studied.     

Development of methods for the synthesis of libraries of substituted maleimides and α,β-unsaturated-γ-butyrolactams

Synthetic methods for the preparation of maleimide and α,β-unsaturated-γ-butyrolactam compound collections are described. These routes take advantage of Pd cross-coupling and conjugate addition/elimination reactions to permit the facile production of bisaryl-maleimides, anilinoaryl-maleimides, and bisanilino-maleimides while allowing control over the synthesis of symmetrical or nonsymmetrical derivatives. Similarly, the chemistry developed allows for the generation of bisaryl substituted α,β-unsaturated-γ-butyrolactams. The scope and limitations of the approaches are presented.     

α-Methylserinals as an access to α-methyl-β-hydroxyamino acids: application in the synthesis of all stereoisomers of α-methylthreonine

The asymmetric synthesis of all stereoisomers of α-methylthreonine using a stereodivergent synthetic route starting from (S)- and (R)-N-Boc-N,O-isopropylidene-α-methylserinals is reported. The key step involves the asymmetric addition of methylmagnesium bromide to these aldehydes with a high level of asymmetric induction being observed. This methodology represents a powerful tool for the synthesis of different β-substituted α-methylserines.     

New method for the synthesis of α-chlorocinnamonitriles

A novel method for the preparation of nitriles of -chlorocinnamic acid from aldehydes and ketones was proposed. Transformation of carbonyl compounds into hydrazones followed by treatment of the reaction mixture with CCl₃CN in the presence of copper chloride(i) yields -chlorocinnamonitriles.     

Organocatalytic asymmetric halogenation/semipinacol rearrangement: highly efficient synthesis of chiral α-oxa-quaternary β-haloketones

A novel asymmetric halogenation/semipinacol rearrangement reaction catalyzed by cinchona alkaloid derivatives was developed. Two types of β-haloketones (X = Br, Cl) were obtained with up to 95% yield and 99% enantiomeric excess. The desired (+) and (-) enantiomers of the β-haloketones were readily obtained.     

Cyclic chlorophosphites as scaffolds for the one-pot synthesis of α-aminophosphonates under solvent-free conditions

New α-aminophosphonates of the type (OCH₂CMe₂CH₂O)P(O)CH(NHCO₂R)(R′) [6a-i, 7a-e, and 8a-c] have been synthesized in high yields by a three-component reaction using (OCH₂CMe₂CH₂O)PCl (3), benzamide (or urethane or benzyl carbamate), and an aldehyde without using any catalyst under solvent-free conditions. This route can be readily adapted for bis-aminophosphonates as well as optically active binaphthoxy α-aminophosphonates; it also tolerates the phenolic -OH group as shown by the synthesis of hydroxy functionalized aminophosphonates. Partial hydrolysis of compounds 7a-d leads to products in which the phosphorinane ring is cleaved first. Compounds (OCH₂CMe₂CH₂O)P(O)CH[NHC(O)Ph](9-anthryl) (6f) and optically pure (R,S)-(−)-(C₂₀H₁₂O₂)P(O)CH(NHCO₂Et)(Ph) (14a) were characterized by X-ray crystallography.     

N-Substituted C-diethoxyphosphorylated nitrones as useful synthons for the synthesis of α-aminophosphonates

A convenient method for the synthesis of N-substituted C-phosphorylated nitrones 2 from hydroxymethylphosphonates via successive Swern oxidation and treatment with respective hydroxylamines is reported for the first time. Moderate (20%) to excellent (up to 90%) diastereoselectivities in cycloadditions of nitrone 2a and terminal alkenes were observed with trans C5-substituted isoxazolidines predominating. In ZnCl₂-catalysed cycloadditions, mixtures enriched in cis diastereoisomers were produced.     

Facile synthesis of biotin-labelled α-galactosylceramide as antigen for invariant natural killer T cells

When iNKT cells are stimulated by the CD1d presented exogenous α-galactosylceramide, a myriad of cytokines are released that trigger a variety of immune responses. However, the invisibility and poor aqueous solubility of α-galactosylceramide during bioassays have rendered it difficult to study the aforementioned biological responses. Accordingly, a biotin-labelled α-galactosylceramide was prepared to facilitate detection of this antigen in the immune process. The problematic low solubility was also remedies via incorporation of a truncated acyl chain.     

Design and synthesis of novel α-aminoamides derivatives as Nav1.7 inhibitors for antinociception

Three novel series of α-aminoamides derivatives were designed and synthesized based on ralfinamide,and their Nav1.7 inhibitory activities were evaluated using manual patch clamp electrophysiology. Active compounds inhibited Nav1.7 with half maximal inhibitory concentration(IC50) values ranging from2.9 μmol/L to 21.4 μmol/L. Among them, the most potent compound 19h exhibited about 12-fold potency better than ralfinamide. The investigation of their structure-activity relationship gives a strategy ...