Synthesis and Biological Evaluation of Lactimidomycin and Its Analogues

The studies culminating in the total synthesis of the glutarimide‐containing eukaryote translation elongation inhibitor lactimidomycin are described. The optimized synthetic route features a Zn^II‐mediated intramolecular Horner–Wadsworth–Emmons (HWE) reaction resulting in a highly stereoselective formation of the strained 12‐membered macrolactone of lactimidomycin on a 423 mg scale. The presence of the E,Z‐diene functionality was found to be key for effective macrocyclizations as a complete removal of these unsaturation units resulted in exclusive formation of the dimer rather than monocyclic enoate. The synthetic route features a late‐stage installation of the glutarimide functionality via an asymmetric catalytic Mukaiyama aldol reaction, which allows for a quick generation of lactimidomycin homolog 55 containing two additional carbons in the glutarimide side chain. Similar to lactimidomycin, this analog was found to possess cytotoxicity against MDA‐MB‐231 breast cancer cells (GI₅₀=1–3 μM) using in vitro 2D and 3D assays. Although lactimidomycin was found to be the most potent compound in terms of anticancer activity, 55 as well as truncated analogues 50 – 52 lacking the glutarimide side‐chain were found to be significantly less toxic against human mammary epithelial cells.     

Total and Semi‐Syntheses of Antimicrobial Thuggacin Derivatives

The total and semi‐synthesis of 13 new macrolactones derived from thuggacin, which is a secondary metabolite from the myxobacterium Sorangium cellulosum, are reported. The thuggacins have attracted much attention due to their strong antibacterial activity, particularly towards Mycobacterium tuberculosis. This study focuses on 1) thuggacin derivatives that cannot equilibrate by transacylation between the three natural thuggacins A–C, 2) the roles of the thiazole ring, and 3) the hexyl side chain at C2. Semi‐synthetic O‐methylation at C17 suppressed the transacylations without a substantial loss of antibacterial activity. Exchanging the C17–C25 side chain for simplified hydrophobic chains led to complete loss of antibacterial activity. Exchange of the thiazole by an oxazole ring or removal of the hexyl side chain at C2 had no substantial effect on the biological properties.     

Synthesis of New 9‐Methylene Analogs of Retinoids

We report herein a series of syntheses that provides diverse structural modifications of the side‐chain of retinoids to obtain new compounds with potential use in anticancer therapy. Starting from a β‐methylenealdehyde synthon, we have synthesized a series of new 9‐methylene‐13‐desmethyl‐14‐methyl analogs and a series of 9‐methylene‐11‐desmethyl trienic homologs. For the first series, the condensation of the C‐15 β‐methylenealdehyde with the anion of ethyl 4‐(diethoxyphosphoryl)‐2E‐methylbut‐2‐enoate led to the 7E,11E,13E‐ester. This gave the desired aldehyde by a reduction into the corresponding alcohol (DIBAL‐H) and subsequent oxidation by MnO₂. For the second series, the reaction of the C‐15 β‐methylenealdehyde with the anions of ethyl diethoxyphosphorylacetate, diethyl cyanomethylphosphonate, or diethyl 2‐oxopropylphosphonate led to the C‐17 ester, the C‐17 nitrile, and the C‐18 ketone, respectively.     

Total synthesis of akuammiline alkaloid (+)-strictamine

An asymmetric total synthesis of the akuammiline alkaloid (+)-strictamine is described. The key steps of the synthetic route involve an improved Johnson-Claisen rearrangement to facilitate the formation of the challenging C15–C20 linkage and the (E)-alkene side chain, intramolecular nucleophilic substitution cyclization to establish the E ring and diastereoselective Brown hydroboration of the terminal alkene to introduce the C16 stereocenter.     

Total syntheses of four possible stereoisomers of resolvin E3

Resolvin E3, 17,18-dihydroxy-5Z,8Z,11Z,13E,15E-eicosapentaenoic acid, is a potent anti-inflammatory lipid mediator. To determine the stereochemistries of the C17- and C18-hydroxy groups of resolvin E3 and to supply a sufficient amount of material for future biological studies, we developed a highly convergent and practical route to its four possible stereoisomers. The key reactions employed here were the Horner–Wadsworth–Emmons coupling, the two copper(I)-mediated reactions between the alkynes and the propargyl tosylates, and the simultaneous reduction of the three triple bonds to the three Z-olefins.     

General Route for the Preparation of Diverse 17-Membered Macrocycles Based on RCM and Examination of the E/Z Selectivity

A convergent, general synthetic route to 17-membered macrocycles was developed to support biological evaluation and structure–activity relationship (SAR) studies during phenotypic screening for immunology targets. A series of amide coupling reactions led to a ring-closing metathesis (RCM) precursor that was cyclized using Grubbs' catalysts. It was found that the reaction formed the macrocyclic products in a 3:1 ratio of E/Z isomers. Moreover, it was shown that a number of similarly substituted RCM precursors undergo cyclization to produce the geometric E/Z isomers in roughly the same 3:1 ratio. The remarkable independence of the E/Z outcome from the substitution pattern of the RCM precursor makes this synthetic approach generally applicable. Separation of the E/Z isomers was achieved by preparative high-performance liquid chromatography and allowed biological profiling of the geometric isomers. Reactive groups in the macrocycle were utilized for late-stage modifications in the fashion of diversity-orientated synthesis (DOS), yielding analogs for SAR studies.     

Total Synthesis,Stereochemical Assignment,and Field‐Testing of the Sex Pheromone of the Strepsipteran Xenos peckii

The sex pheromone of the endoparasitoid insect Xenos peckii (Strepsiptera: Xenidae) was recently identified as (7E,11E)‐3,5,9,11‐tetramethyl‐7,11‐tridecadienal. Herein we report the asymmetric synthesis of three candidate stereostructures for this pheromone using a synthetic strategy that relies on an sp³–sp² Suzuki–Miyaura coupling to construct the correctly configured C7‐alkene function. Comparison of ¹H NMR spectra derived from the candidate stereostructures to that of the natural sex pheromone indicated a relative configuration of (3R*,5S*,9R*). Chiral gas chromatographic (GC) analyses of these compounds supported an assignment of (3R,5S,9R) for the natural product. Furthermore, in a 16‐replicate field experiment, traps baited with the synthetic (3R,5S,9R)‐enantiomer alone or in combination with the (3S,5R,9S)‐enantiomer captured 23 and 18 X. peckii males, respectively (mean±SE: 1.4±0.33 and 1.1±0.39), whereas traps baited with the synthetic (3S,5R,9S)‐enantiomer or a solvent control yielded no captures of males. These strong field trapping data, in combination with spectroscopic and chiral GC data, unambiguously demonstrate that (3R,5S,9R,7E,11E)‐3,5,9,11‐tetramethyl‐7,11‐tridecadienal is the X. peckii sex pheromone.     

Synthesis of 11-aza-artemisinin derivatives using the Ugi reaction and an evaluation of their antimalarial activity

A series of new 11-aza-artemisinin derivatives were prepared from 11-aza-artemisinin using the Ugi reaction. An antimalarial activity evaluation against the FcB1 strain indicated that compounds 7, 10, and 16 had very strong inhibitory activity. Comparison of the activity among the synthetic derivatives of this series revealed that the length of the side chain R group on the amide nitrogen could be critical for their antimalarial properties.     

A Modular Synthesis of Conformationally Preorganised Extended β‐Strand Peptidomimetics

A promising strategy for mediating protein–protein interactions is the use of non‐peptidic mimics of secondary structural protein elements, such as the α‐helix. Recent work has expanded the scope of this approach by providing proof‐of‐principle scaffolds that are conformationally biased to mimic the projection of side‐chains from one face of another common secondary structural element—the β‐strand. Herein, we present a synthetic route that has key advantages over previous work: monomers bearing an amino acid side‐chain were pre‐formed before rapid assembly to peptidomimetics through a modular, iterative strategy. The resultant oligomers of alternating pyridyl and six‐membered cyclic ureas accurately reproduce a recognition domain of several amino acid residues of a β‐strand, demonstrated herein by mimicry of the i, i+2, i+4 and i+6 residues.     

Conformational preference and mechanism of decarboxylation of levodopa. A quantum dynamics/quantum mechanics study

The present study addresses the conformational preferences and the mechanism of decarboxylation of levodopa (LD). LD is used to increase dopamine concentrations in the treatment of Parkinson's disease. LD crosses the protective blood–brain barrier, where it is converted into dopamine by the process of decarboxylation. Molecular dynamics simulation has been carried out at the DFT/6‐31++G level of theory to identify the global minimum structure of LD. Conformational preferences of the amino acid side chain of LD has been investigated at the B3LYP/6‐311++G** level of theory. Fourier transform analysis has been performed to identify the origin of the rotational barriers. Electrostatic dipole moment and bond interactions underlie the observed potential energy barriers for rotation of the amino acid side chain of LD. The vital biological process of decarboxylation of LD has been examined in the gas phase and in aqueous solution. Without the presence of water, there is only one possible route for the decarboxylation of LD. In this concerted mechanism, a proton transfer and breakage of the C₁₀—C₁₈ bond, take place simultaneously (ΔE^# = 73.2 kcal/mol). In solution, however, two possible decarboxylation routes are available for LD. The first involve the formation of a zwitterionic intermediate (ΔE^# = 72.4 kcal/mol). The zwitterionic form of LD have been localized using explicitly bound water molecules to model short‐range solvent effects and self‐consistent reaction field polarized continuum model to estimate long‐range solvent interactions. The second route involve the formation of a cyclic structure in which a water molecule acts as a bridge linking the anticarboxylic hydrogen and α‐position carbon atom (ΔE^# = 59.8 kcal/mol). Natural bond orbital (NBO) analysis reveals that the conformational and overall stability of the amino acid side chain is facilitated by the antiperiplanar interactions between the phenyl moiety C—H and C—C bonds and C—X bonds of the amino acid side chain. However, much of the major donor–acceptor interactions is of the lone pair type and is localized within the amino acid side chain itself. Results of the present work reveal that NBO data reflect nicely and identify clearly reaction coordinates at the transition species. © 2013 Wiley Periodicals, Inc.     

X-Ray Structure Analysis of 15-Apoviolaxanth-15-al

The X-ray structure of 15-apoviolaxanth-15-al ( = (1′S,2′R,4′S,2E,4E,6E,8E)-9-(1′,2′-epoxy-4′-hydroxy-2′,6′,6′-trimethylcyclohexyl)-3,7-dimethylnona-2,4,6,8-tetraenal) is reported. The four symmetry-independent molecules in the asymmetric unit are linked into X-shaped spirals by intermolecular H-bonds. Additional H-bonds interconnect the spirals, forming wave-like chains. The geometry of the polyene side chain possesses the same in-plane bending observed for related retinal and carotenoid compounds. The polyene side chain deviates from planarity by twists of up to 10° about each bond; some of the largest twists are about C?C bonds. The epoxycyclohexane ring possesses a distorted ‘C(3)-sofa’ conformation. The torsion angles about the bond connecting the polyene chain to the cyclohexane ring are compared with equivalent torsion angles in molecules containing epoxide rings substituted with a π-system in order to examine possible interactions between the epoxide group and the π-system, either through pseudoconjugation, or through an interaction of the nonbonding orbitals of the epoxy O-atom with the π-orbitals of the polyene chain. The latter is considered to be more likely.     

Revealing the effect of oligo(ethylene glycol) side chains on n-doping process in FBDPPV-based polymers

The low doping efficiency of n-doped systems limits the development of n-type organic conducting materials. Oligo(ethylene glycol) (OEG) as the flexible chain in conjugated small molecules and polymers may improve doping efficiency. However, OEG side chains also bring unexpected low mobility and poor film morphology. Herein, we propose the stronger solution-state aggregation plays a dominated role in charge transport and morphology of OEG-substituted polymer. The solution-state aggregation also affects doping process. Therefore, we develop a series of polymers based on 3,7-bis((E)-7-fluoro-1-(2-octyldodecyl)-2-oxoindolin-3-ylidene)-3,7-dihydrobenzo[1,2-b:4,5-b']difuran-2,6-dione (FBDPPV) with different ratios of OEG side chain to investigate the effect of side chain on solution-state aggregation and n-doping process. After n-doped by hexahydro-1H,3a1H,4H,7H-3a,6a,9a-triazaphenalene (TAM), FBDPPV with 50% OEG affords the highest doping efficiency and conductivity, while FBDPPV with 100% OEG shows lower conductivity. Combination of ultraviolet–visible–near infrared absorption spectra, grazing-incidence wide-angle X-ray scattering and atomic force microscopy, we reveal that serious aggregated extent in solution of OEG-substituted polymer result in phase separation and rough morphology, which are the origins of poor conductivity. Our work provides a new perspective on the effect of the OEG side chain on the doped polymer systems, suggesting suitable solution-state aggregation is crucial to high doping efficiency and high conductivity.     

Synthesis and properties of nonlinear optical side chain soluble polyimides for photonics applications

Aromatic polyimides with side chain nonlinear optical chromophores have been investigated through a facile two-step synthetic route. First, various poly(hydroxy imide)s have been synthesized by direct thermal imidization of diaminophenol dihydrochloride salt and aromatic dianhydride monomers. The resulting polyimides bearing phenolic hydroxy groups were found to react easily with the terminal hydroxy group on the chromophores via the Mitsunobu condensation to give corresponding polyimides with high optical nonlinearities and good solubility in common organic solvents. Detailed physical properties showed that these polyimides have a molecular weight (M_w) of 31,000 and high glass transition temperature above 220°C, ensuring a long-term alignment stability at elevated temperature. The electrooptic coefficients, r₃₃, of the electrically poled polymer films were in the range 1.8–7.6 pm/V at 1.3 μm. © 1998 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 36: 301–307, 1998     

Syntheses and characterizations of aniline/butylthioaniline copolymers: Comparisons of copolymers prepared by the new concurrent reduction and substitution route and the conventional oxidative copolymerization method

New highly solution‐processable aniline/butylthioaniline copolymers were prepared via oxidative copolymerization (OCP) and by concurrent reduction and substitution (CRS). Butylthio‐substituted polyaniline obtained via the CRS route (Pan‐SBu), being in line with the expected property changes after the addition of an electron‐donating substituent to an aromatic ring, displayed a lowered redox potential (E⁰) and a redshifted maximum wavelength (λ_max; ultraviolet–visible) in comparison with its parent unsubstituted polyaniline (Pan). However, copolymers CP1–CP4 (obtained via the OCP method) displayed opposite behaviors, showing higher E⁰ values and blueshifts in λ_max than the unsubstituted Pan. The results suggested that CP1–CP4 had shorter conjugation lengths than the unsubstituted Pan, possibly because of their chain conjugation defects (e.g., 1,3‐ring linkage structures), as evidenced by IR studies. The results of ¹H NMR studies also indicated that Pan‐SBu had much higher structural homogeneity than copolymer CP4. Because the CRS synthetic route involved no backbone alternations, the resultant copolymer (Pan‐SBu) should have maintained the same backbone structure and hence the high conductivity of the parent unsubstituted Pan. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 1767–1777, 2005     

Structural aspects of two α‐dihydrazones displaying a complete survey of intermolecular interactions

The compounds (2′E,2′E)‐2,2′‐(propane‐1,2‐diylidene)bis[1‐(2‐nitrophenyl)hydrazine], C₁₅H₁₄N₆O₄, (I), and (2Z,3Z)‐ethyl 3‐[2‐(2‐nitrophenyl)hydrazinylidene]‐2‐[2‐(4‐nitrophenyl)hydrazinylidene]butanoate tetrahydrofuran hemisolvate, C₁₈H₁₈N₆O₆·0.5C₄H₈O, (II), are puzzling outliers deviating from a general synthetic route aimed at the preparation of substituted pyrazoles. Possible reasons for this outcome, which is exceptional in an otherwise firmly established synthetic procedure, are analyzed. Compound (I) is unsolvated, while compound (II) crystallizes with a tetrahydrofuran solvent molecule lying on an inversion centre. The ethoxycarbonyl chain of (II), in turn, appears disordered into two equally populated (50%) moieties. In both structures, a plethora of different commonly occurring weak intermolecular interactions [viz. π(phenyl)...π(phenyl), π(C=N)...π(C=N), π(phenyl)...π(C=N), N—H...O and C—H...O] appear responsible for the crystal stability. Much less common are the short O(nitro)...O(nitro) contacts which are observed in the structure of (I), an example of unusual `electron donor–acceptor' (EDA) interactions.     

Synthesis and characterizations of new isotactic homopolyesters,statistical and block copolyesters derived of poly((S)‐3,3‐dimethylmalic acid) via the lactone route

This article presents the synthesis of a new family of synthetic isotactic polyesters derived from poly((S)‐3,3‐dimethylmalic acid) (PDMMLA). These polyesters are prepared via the lactone route bearing functionalized groups in its main or side chain. The aim of this work is twofold: metabolism and stereochemistry. First, the synthesis of these new polyesters is chosen to provide biodegradable polyesters biocompatible and bioassimilable by the human body. Next, the molecular chain of this family contains a stereogenic center in the aim to provide 100% isotactic homopolymers and copolymers (statistical and block). Finally, these polymers have been characterized by several analytical techniques: FTIR, ¹H and ¹³C NMR, SEC, DSC, and TGA. The greatest importance will be given to the ¹³C NMR and DSC to principally confirm the stereoregularity and crystallinity of these stereopolyesters. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 1495–1507     

Highly trans‐Selective Arylation of Achmatowicz Rearrangement Products by Reductive γ‐Deoxygenation and Heck–Matsuda Reaction: Asymmetric Total Synthesis of (−)‐Musellarins A–C and Their Analogues

Fully functionalized pyranuloses derived from Achmatowicz rearrangement (AR) are versatile building blocks in organic synthesis. However, access to trans‐2,6‐dihydropyrans from pyranuloses remains underexplored. Herein, we report a new two‐step trans arylation of AR products to access 2,6‐trans‐dihydropyranones. This new trans‐arylation method built on numerous plausible, but unsuccessful, direct arylation reactions, including Ferrier‐type and Tsuji–Trost‐type reactions, was finally enabled by an unprecedented, highly regioselective γ‐deoxygenation of AR products by using Zn/HOAc and a diastereoselective Heck–Matsuda coupling. The synthetic utility of the reaction was demonstrated in the first asymmetric total synthesis of (?)‐musellarins A–C and 12 analogues in 11–12 steps. The brevity and efficiency of our synthetic route permitted preparation of enantiomerically pure musellarins and analogues (>20 mg) for preliminary cytotoxicity evaluation, which led us to identify two analogues with three‐to‐six times greater potency than the musellarins as promising new leads.     

A study on the sulfenylchlorination of cembrene and the related cembranoids

p-Tolylsulfenyl chloride adds regioselectively at the C(11) ? C(12) bond of cembrene 1 to give 11-(R)-p-tolylthio-1-(S)-cembra-2E, 4Z, 7E, 12(20)-tetraene 2 following a rapid HCl elimination. Two new cembranoids, 1-(S)-cembra-2E, 4Z, 7E, 12(20)-tetraene 3 and 1-(S)-cembra-2E, 4Z, 7E, 11Z-tetraen-20-ol 4 are prepared from 2.     

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 ).     

Synthesis,Profiling, and Bioactive Conformation of trans‐Cyclopropyl Epothilones

A series of new 3‐deoxy‐C(12),C(13)‐trans‐cyclopropyl‐epothilones have been prepared, bearing benzothiazole, quinoline, thiazol‐5‐ylvinyl, or isoxazol‐3‐ylvinyl side chains. For analogs with fused aromatic side chains, macrocyclic ring‐closure was based on ring‐closing olefin metathesis (RCM) of a precursor incorporating the fully elaborated heavy atom framework of the target structure (including the side chain moiety), while side chain attachment for the thiazole and isoxazole‐containing 16‐desmethyl analogs was performed only after establishment of the macrolactone core. Two approaches were elaborated for a macrocyclic aldehyde as the common precursor for the latter analogs that involved ring‐closure either by RCM or by macrolactonization. Benzothiazole‐ and quinoline‐based analogs were found to be highly potent antiproliferative agents; the two analogs with a thiazol‐5‐ylvinyl or an isoxazol‐3‐ylvinyl side chain likewise showed good antiproliferative activity but were significantly less potent than the parent epothilone A. Surprisingly, the desaturation of the C(10)?C(11) bond in these analogs was associated with a virtually complete loss in antiproliferative activity, which likely reflects a requirement for a ca. 60 ° C(10)?C(11) torsion angle in the tubulin‐bound conformation of 12,13‐trans‐epothilones.