Synthesis of Racemic Δ3‐2‐Hydroxybakuchiol and Its Analogues

The first synthetic approach to (±)‐Δ³‐2‐hydroxybakuchiol (=4‐[(1E,5E)‐3‐ethenyl‐7‐hydroxy‐3,7‐dimethylocta‐1,5‐dien‐1‐yl]phenol; 14 ) and its analogues 13a – 13f was developed by 12 steps (Schemes 2 and 3). The key features of the approach are the construction of the quaternary C‐center bearing the ethenyl group by a Johnson–Claisen rearrangement (→ 6 ); and of an (E)‐alkenyl iodide via a Takai–Utimoto reaction (→ 11 ); and an arylation via a Negishi cross‐coupling reaction (→ 12e – 12f ).     

Total Synthesis of (+)‐β‐Himachalene

An enantioselective synthesis of (+)‐β‐himachalene ( 2 ) was accomplished starting from (1S,2R)‐1,2‐epoxy‐p‐menth‐8‐ene ( 3 ) in 15 or 16 steps with an overall yield of ca. 6% (Schemes 3, 5, and 6). Key transformations include an Ireland–Claisen rearrangement, a Corey oxidative cyclization, and a ring expansion.     

Synthesis and Characterization of (–)‐Menthyl Containing N‐Alkyl Cycloimmonium Salts

The reaction of 4‐phenyl‐2‐aminothiazole or 2‐amino pyridine with α‐bromo acetic (–)‐menthyl ester ( 2c ) yields new N‐alkyl cycloimmonium bromides ( 1c , 3 ) with the chiral (–)‐menthyl substituent, which were isolated and fully characterized by ¹H and ¹³C NMR spectroscopy for the first time. In addition, starting from 4‐phenyl‐2‐aminothiazole, two further N‐alkyl cycloimmonium bromides ( 1a , 1b ) were prepared. The molecular and crystal structures of all three thiazole derived N‐alkyl cycloimmonium bromides ( 1a – c ) were determined by single‐crystal X‐ray diffraction. In all cases the crystal structures are dominated by N–H ··· Br hydrogen bonds, which results in the formation of an extensive hydrogen bonded network in the crystal. Interestingly, in all structures S ··· Br^– distances shorter than the sum of the van der Waals radii are observed.     

Effective Methods for the Synthesis of N‐Methyl β‐Amino Acids from All Twenty Common α‐Amino Acids Using 1,3‐Oxazolidin‐5‐ones and 1,3‐Oxazinan‐6‐ones

N‐Methyl β‐amino acids are generally required for application in the synthesis of potentially bioactive modified peptides and other oligomers. Previous work highlighted the reductive cleavage of 1,3‐oxazolidin‐5‐ones to synthesise N‐methyl α‐amino acids. Starting from α‐amino acids, two approaches were used to prepare the corresponding N‐methyl β‐amino acids. First, α‐amino acids were converted to N‐methyl α‐amino acids by the so‐called ‘1,3‐oxazolidin‐5‐one strategy’, and these were then homologated by the Arndt–Eistert procedure to afford N‐protected N‐methyl β‐amino acids derived from the 20 common α‐amino acids. These compounds were prepared in yields of 23–57% (relative to N‐methyl α‐amino acid). In a second approach, twelve N‐protected α‐amino acids could be directly homologated by the Arndt–Eistert procedure, and the resulting β‐amino acids were converted to the 1,3‐oxazinan‐6‐ones in 30–45% yield. Finally, reductive cleavage afforded the desired N‐methyl β‐amino acids in 41–63% yield. One sterically congested β‐amino acid, 3‐methyl‐3‐aminobutanoic acid, did give a high yield (95%) of the 1,3‐oxazinan‐6‐one ( 65 ), and subsequent reductive cleavage gave the corresponding AIBN‐derived N‐methyl β‐amino acid 61 in 71% yield (Scheme 2). Thus, our protocols allow the ready preparation of all N‐methyl β‐amino acids derived from the 20 proteinogenic α‐amino acids.     

Stereocontrolled Total Synthesis of (+)‐trans‐Dihydronarciclasine

A highly stereoselective and efficient total synthesis of trans‐dihydronarciclasine from a readily available chiral starting material was developed. The synthesis defines two of the five stereogenic centers of the natural product by an amino acid ester–enolate Claisen rearrangement. The other three stereogenic centers are created in a highly stereocontrolled fashion via a six‐ring vinylogous ester intermediate, which is generated from the γ,δ‐unsaturated ester functional group of the Claisen rearrangement product in an efficient three‐step sequence. This concise total synthesis exemplifies the use of a highly regioselective Friedel–Crafts‐type cyclization to form the B ring via an isocyanate intermediate derived from an N‐Boc group, which is superior to the conventional method using an imino triflate intermediate. This same N‐Boc group is employed to give high selectivity in the Claisen rearrangement earlier in the sequence.     

Total Synthesis of (2Z)‐[(4R,5R,6S)‐6‐(β‐D‐Glucopyranosyloxy)‐4,5‐dihydroxycyclohex‐2‐en‐1‐ylidene]ethanenitrile,a Cyanoglucoside from Ilex warburgii

The total synthesis of the noncyanogenic cyanoglucoside 1 , originally isolated from Ilex warburgii, was achieved in nine steps (9% overall yield), starting from an optically pure Diels–Alder adduct ((+)‐ 3 ). The key step of the synthesis, the glycosidation, was carried out under Koenigs–Knorr conditions closely related to those developed for the total syntheses of (?)‐lithospermoside and (?)‐bauhinin. We had to tune the protecting groups used for the two free cis‐configured OH groups of the aglycone, which afforded the desired β‐d‐ glucoside intermediate 15 in very good yield (62%).     

Synthesis and Aggregation Behavior of meso‐Sulfinylporphyrins: Evaluation of S‐Chirality Effects on the Self‐Organization to S–Oxo‐Tethered Cofacial Porphyrin Dimers

The synthesis and aggregation behavior of meso‐sulfinylporphyrins are described. The copper‐catalyzed C–S cross‐coupling reaction of a meso‐iodoporphyrin with benzenethiol and n‐octanethiol has proved to be an efficient method for the synthesis of meso‐sulfanylporphyrins, which are oxygenated by m‐chloroperbenzoic acid to produce the corresponding meso‐sulfinylporphyrins. Optically active zinc meso‐sulfinylporphyrins were successfully isolated by means of optical resolution of the racemates on a chiral HPLC column. Zinc sulfinylporphyrins readily undergo self‐organization through S–oxo–zinc coordination to form cofacial porphyrin dimers in solution, in which the hetero‐ and homodimers are present as a diastereomeric mixture. The aggregation modes of the S–oxo‐tethered porphyrin dimers were fully characterized by ¹H NMR, IR, and UV/Vis spectroscopy as well as DFT calculations on their model compounds, thus revealing that the self‐aggregation behavior depends on the combination of S chirality. The absolute configurations at the sulfur center can be determined by the exciton‐coupled CD method. The observed self‐association constant for the S–oxo‐tethered dimerization of (S)‐phenylsulfinylporphyrin in toluene is larger than that in dichloromethane, which reflects the difference in dipole moments between the homodimer and the monomer. In cyclic and differential pulse voltammetry, the first oxidation process of the cofacial dimers is split into two reversible steps, which indicates that the initially produced π radical cations are delocalized efficiently between the two porphyrin rings. The present findings demonstrate the potential utility of meso‐sulfinyl groups as promising ligands for investigating the effects of peripheral chirality on the structures and optical and electrochemical properties of metal‐assisted porphyrin self‐assemblies.     

Synthesis and characterization of biodegradable triblock copolymers based on bacterial poly[(R)‐3‐hydroxybutyrate] by atom transfer radical polymerization

Biodegradable poly(tert‐butyl acrylate)–poly[(R)‐3‐hydroxybutyrate]–poly (tert‐butyl acrylate) triblock copolymers based on bacterial poly[(R)‐3‐hydroxybutyrate] (PHB) were synthesized by atom transfer radical polymerization. The chain architectures of the triblock copolymers were confirmed by ¹H NMR and ¹³C NMR spectra. Gel permeation chromatography analysis was used to estimate the molecular weight characteristics and lengths of the PHB and poly(tert‐butyl acrylate) blocks of the copolymers. The thermal properties of the copolymers were studied by thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). TGA showed that the triblock copolymers underwent stepwise thermal degradation and had better thermal stability than their respective homopolymers, whereas DSC analyses showed that a microphase‐separation structure was formed only in the triblock copolymers with the longer PHB block. As a similar result, from wide‐angle X‐ray diffraction experimentation, the crystalline phase of PHB could not be seen evidently in the triblock copolymers with the shorter PHB block. The enzymatic hydrolysis of the copolymer films was carried at 37 °C and pH 7.4 in a potassium phosphate buffer with an extracellular PHB depolymerase from Penicillum sp. The biodegradability of the triblock copolymers increased with an increase in the PHB block content. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 4857–4869, 2005     

Synthesis of Benzo[g]isochromenes through Photo‐Dehydro‐Diels–Alder Reaction

The Photo‐Dehydro‐Diels–Alder (PDDA) reaction is shown to be a versatile method for the preparation of highly functionalized naphthalenes. Thus, ketones 1 could be cyclized to the 1H‐benzo[g]isochromen‐4‐(3H)‐ones 11 and 12 , mostly in good yields. The influence of various substituents on the regioselectivity of the reaction was investigated, and the mechanism is discussed based on theoretical calculations.     

Total Synthesis of (+)‐Machaeriols B and C and of Their Enantiomers with a Cannabinoid Structure

An efficient and concise synthesis of the biologically interesting (+)‐machaeriol B ( 2 ) and its enantiomer 5 was accomplished from O‐phenylhydroxylamine ( 7 ) in four steps (Scheme 2). In addition, the first total synthesis of natural (+)‐machaeriol C ( 3 ) and its enantiomer 6 was achieved from the readily available ester 15 in eight steps (Scheme 4). The key strategies in the syntheses of 2 and 5 involved benzofuran formation through a [3,3]‐sigmatropic rearrangement and trans‐hexahydrodibenzopyran formation by a domino aldol‐type/hetero‐Diels–Alder reaction. In the case of 3 and 6 , the key steps were stilbene formation by a Horner–Wadsworth–Emmons reaction and trans‐hexahydrodibenzopyran formation by domino reactions.     

Classical Benzotriazole‐Mediated α‐Aminoalkylations of Alkynes: Synthesis and Characterization of Alk‐2‐yn‐1‐amines as Amphiphilic Materials

Reactions of readily available and stable benzotriazolemethanamines 1a – l , obtained from aldehydes and secondary amines (Scheme 2), gave the expected alk‐2‐yn‐1‐amines 3a – t (Scheme 3). The amphiphilic character of the synthesized products was responsible for physicochemical measurements. Specific aggregation properties of the obtained compounds make them useful as electroactive materials in the Langmuir–Blodgett technique.     

Application of a LC–MS/MS method developed for the determination of p‐phenylenediamine,N‐acetyl‐p‐phenylenediamine and N,N‐diacetyl‐p‐phenylenediamine in human urine specimens

Cases of poisoning by p‐phenylenediamine (PPD) are detected sporadically. Recently an article on the development and validation of an LC–MS/MS method for the detection of PPD and its metabolites, N‐acetyl‐p‐phenylenediamine (MAPPD) and N,N‐diacetyl‐p‐phenylenediamine (DAPPD) in blood was published. In the current study this method for detection of these compounds was validated and applied to urine samples. The analytes were extracted from urine samples with methylene chloride and ammonium hydroxide as alkaline medium. Detection was performed by LC–MS/MS using electrospray positive ionization under multiple reaction‐monitoring mode. Calibration curves were linear in the range 5–2000 ng/mL for all analytes. Intra‐ and inter‐assay imprecisions were within 1.58–9.52 and 5.43–9.45%, respectively, for PPD, MAPPD and DAPPD. Inter‐assay accuracies were within ?7.43 and 7.36 for all compounds. The lower limit of quantification was 5 ng/mL for all analytes. The method, which complies with the validation criteria, was successfully applied to the analysis of PPD, MAPPD and DAPPD in human urine samples collected from clinical and postmortem cases.     

Synthesis and antimicrobial activity of bulky 3,5‐di‐tert‐butyl substituent‐containing silver–N‐heterocyclic carbene complexes

A series of novel benzimidazolium bromides containing bulky 3,5‐di‐tert ‐butyl group were synthesized in high yields as N‐heterocyclic carbene (NHC) ligands. These NHC ligands were metallated with Ag₂O under moderate conditions to give novel silver–NHC complexes. The structures of all compounds were characterized using ¹H NMR, ¹³CNMR, infrared and elemental analysis techniques, which supported the proposed structures. The silver–NHC complexes were screened for their in vitro antimicrobial activities against the standard bacterial strains Enterococcus faecalis , Staphylococcus aureus , Escherichia coli and Pseudomonas aeruginosa and the fungal strains Candida albicans and C. tropicalis . The results showed that most of the silver–NHC complexes inhibited the growth of all bacterial strains and fungal strains and were found to display effective antimicrobial activity against different microorganisms.     

A rapid and sensitive LC–MS/MS method for quantification of quercetin‐3‐O‐β‐d‐glucopyranosyl‐7‐O‐β‐d‐gentiobioside in plasma and its application to a pharmacokinetic study

A rapid and sensitive LC–MS/MS method with good accuracy and precision was developed and validated for the pharmacokinetic study of quercetin‐3‐O‐β‐d ‐glucopyranosyl‐7‐O‐β‐d ‐gentiobioside (QGG) in Sprague–Dawley rats. Plasma samples were simply precipitated by methanol and then analyzed by LC–MS/MS. A Venusil® ASB C₁₈ column (2.1 × 50 mm, i.d. 5 μm) was used for separation, with methanol–water (50:50, v/v) as the mobile phase at a flow rate of 300 μL/min. The optimized mass transition ion‐pairs (m/z) for quantitation were 787.3/301.3 for QGG, and 725.3/293.3 for internal standard. The linear range was 7.32–1830 ng/mL with an average correlation coefficient of 0.9992, and the limit of quantification was 7.32 ng/mL. The intra‐ and inter‐day precision and accuracy were less than ±15%. At low, medium and high quality control concentrations, the recovery and matrix effect of the analyte and IS were in the range of 89.06–92.43 and 88.58–97.62%, respectively. The method was applied for the pharmacokinetic study of QGG in Sprague–Dawley rats. Copyright © 2016 John Wiley & Sons, Ltd.     

Synthesis of poly(3‐hexylthiophene)‐block‐poly(ethylene)‐block‐poly(3‐hexylthiophene) via a combination of ring‐opening olefin metathesis polymerization and grignard metathesis polymerization

Novel rod–coil–rod ABA triblock copolymers, poly(3‐hexylthiophene)‐block‐poly(ethylene)‐block‐poly(3‐hexylthiophene) (P3HT‐b‐PE‐b‐P3HT) were synthesized by using a combination of a Ru‐catalyzed ring‐opening metathesis polymerization of 1,4‐cyclooctadiene in the presence of a suitable chain transfer agent (CTA) and a Ni‐catalyzed Grignard metathesis polymerization of 5‐chloromagnesio‐2‐bromo‐3‐hexylthiophene followed by hydrogenation. Using this methodology, the molecular weights of the poly(butadiene) (PBD) or the P3HT blocks were controlled by adjusting the initial monomer/CTA or the initial monomer/macroinitiator ratio, respectively. In addition, the triblock structure was confirmed by selective oxidative degradation of the PBD block found in the intermediate P3HT‐b‐PBD‐b‐P3HT copolymer produced in the aforementioned method, followed by analysis of the degradation products. Thermal analysis and atomic force microscopy of P3HT‐b‐PE‐b‐P3HT revealed that the material underwent phase separation in the solid state, a feature which may prove useful for improving charge mobilities within electronic devices. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013 , 51, 3810–3817     

Enantioselective Synthesis of (−)‐(19R)‐Ibogamin‐19‐ol

The first total synthesis of the natural product (?)‐(19R)‐ibogamin‐19‐ol ((?)‐ 1 ) is reported (biogenetic atom numbering). Starting with L ‐glutamic acid from the chiral pool and (2S)‐but‐3‐en‐2‐ol, the crucial aliphatic isoquinuclidine (= 2‐azabicyclo[2.2.2]octane) core containing the entire configurational information of the final target was prepared in 15 steps (overall yield: 15%). The two key steps involved a highly effective, self‐immolating chirality transfer in an Ireland–Claisen rearrangement and an intramolecular nitrone‐olefin 1,3‐dipolar cycloaddition reaction (Scheme 3). Onto this aliphatic core was grafted the aromatic moiety in the form of N(1)‐protected 1H‐indole‐3‐acetic acid by application of the dicyclohexylcarbodiimide (DCC) method (Scheme 4). Four additional steps were required to adjust the substitution pattern at C(16) and to deprotect the indole subunit for the closure of the crucial 7‐membered ring present in the targeted alkaloid family (Schemes 4 and 5). The spectral and chiroptical properties of the final product (?)‐ 1 matched the ones reported for the naturally occurring alkaloid, which had been isolated from Tabernaemonatana quadrangularis in 1980. The overall yield of the entire synthesis involving a linear string of 20 steps amounted to 1.9% (average yield per step: 82%).     

Intramolecular Hetero‐Diels–Alder Reactions Catalyzed by BiCl3: Stereoselective Synthesis of Benzo‐Annelated Decahydrofuro[3,2‐h][1,6]naphthyridine Derivatives

A novel, efficient synthesis of a series of functionalized, benzo‐annelated decahydrofuro[3,2‐h][1,6]naphthyridine derivatives 3 has been achieved. The protocol is based on the intramolecular hetero‐Diels–Alder (IMHDA) reaction of in situ formed imines derived from an N‐prenylated sugar aldehyde 1 and different aromatic amines 2 in the presence of bismuth(III) chloride as catalyst. The reactions could be run under very mild conditions at room temperature, and were complete within 30 min, affording exclusively and stereoselectively the corresponding trans‐fused products 3 in good‐to‐excellent yields (Table).     

From Linear to T‐Shaped Indan‐1,3‐dione Push–Pull Molecules: A Comparative Study

A series of indan‐1,3‐dione‐based linear, quadrupolar and T‐shaped push–pull chromophores have been designed and synthesized by the Knoevenagel condensation and Pd‐catalyzed Suzuki–Miyaura or Sonogashira cross‐coupling reactions. The number and position of the peripheral donor branches attached to the central withdrawing indan‐1,3‐dione moiety have been varied jointly with the type of π‐linker used in order to modulate fundamental optoelectronic properties. The molecular structure of two chromophores has been confirmed by X‐ray analysis. The thermal and optoelectronic properties have further been investigated by differential scanning calorimetry, electrochemistry, UV/Vis absorption spectroscopy, and DFT calculations. Based on these experimental and theoretical data, thorough structure–property relationships have been further evaluated and influence of the particular structural modification on chromophore properties has been discussed.     

Synthesis and characterization of novel aromatic polyimides from 4,4‐bis(p‐aminophenoxymethyl)‐ 1‐cyclohexene

A novel diamine, 4,4‐bis(p‐aminophenoxymethyl)‐1‐cyclohexene (CHEDA), was synthesized from 4,4‐bis(hydroxymethyl)‐1‐cyclohexene and p‐chloronitrobenzene by nucleophilic aromatic substitution and subsequent catalytic reduction of the intermediate dinitro compound. A series of aromatic polyimides were prepared from CHEDA and commercial dianhydrides with varying flexibility and electronic character in two‐step direct polycondensation reactions. High molecular weight polyimides with intrinsic viscosities between 0.57 and 10.2 dL/g were obtained. Most of these polyimides, excluding those from PMDA and BPDA, were soluble in polar aprotic solvents such as NMP and DMAc, and many were also soluble in CHCl₃ and THF. DSC analysis revealed glass transitions in the range of 190 to 250°C. No significant weight losses occurred below 450°C in nitrogen and 350°C in air. Bromination and epoxidation of cyclohexene double bond in CHDEA–6FDA (3e) were investigated as examples of possible polymer modifications. Qualitative epoxidation and selective bromination of the double bond were demonstated. © 1999 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 37: 1189–1197, 1999     

Luminescent Quadrupolar Borazine Oligomers: Synthesis,Photophysics, and Two‐Photon Absorption Properties

A set of monodisperse bent donor–acceptor–donor‐type conjugated borazine oligomers, BnNn+1 (n=1–4), incorporating electron‐rich triarylamine donor and electron‐deficient triarylborane acceptor units has been prepared through an iterative synthetic approach that takes advantage of highly selective silicon–boron and tin–boron exchange reactions. The effect of chain elongation on the electrochemical, one‐ and two‐photon properties and excited‐state photodynamics has been investigated. Strong intramolecular charge transfer (ICT) from the arylamine donors to boryl‐centered acceptor sites results in emissions with high quantum yields (Φ_fl>0.5) in the range of 400–500 nm. Solvatochromic effects lead to solvent shifts as large as ～70 nm for the shortest member (n=1) and gradually decrease with chain elongation. The oligomers exhibit strong two‐photon absorption (2PA) in the visible spectral region with 2PA cross sections as large as 1410 GM (n=4), and broadband excited‐state absorption (ESA) attributed to long‐lived singlet–singlet and radical cation/anion absorption. The excited‐state dynamics also show sensitivity to the solvent environment. Electrochemical observations and DFT calculations (B3LYP/6‐31G*) reveal spatially separated HOMO and LUMO levels resulting in highly fluorescent oligomers with strong ICT character. The BnNn+1 oligomers have been used to demonstrate the detection of cyanide anions with association constants of log K>7.