Advanced Precursor Research Articles

ChemInform Abstract: The Palladium Way to N‐Heteroacenes

AbstractReview: [25 refs.

Chemoenzymatic Access to (+)-Artabotriol and its Application in Collective Synthesis of (+)-Grandiamide D, (–)-Tulipalin B, (+)-Spirathundiol, and (+)-Artabotriolcaffeate

Starting from dimethyl (±)-2-hydroxy-3-methylenesuccinnate chemoenzymatic collective formal/total synthesis of enantiomerically pure bioactive natural products has been described via the advanced level common precursor (+)-artabotriol. An efficient enzymatic resolution with high enantiomeric purity, selective diester to diol reduction, and requisite dehydrative coupling reactions without any racemization are the significant topographies.

Gold(I)-Catalyzed Enyne Cyclizations: Studies Toward the Total Synthesis of (+)-Aureol

We report a modular synthetic approach toward the total synthesis of (+)-aureol based on a bioinspired gold(I)-catalyzed enyne cascade cyclization reaction. First, we investigated an array of catalysts to promote a 6-<i>endo</i>-dig cyclization of a highly advanced enediyne precursor. Since these studies result exclusively in the formation of the 5-<i>exo</i>-dig product, we synthesized and investigated a dienyne cyclization precursor in order to form the benzo[<i>d</i>]xanthene skeleton in a stepwise fashion.

The Palladium Way to N-Heteroacenes.

Novel synthetic methodologies allow increasingly efficient access to known organic materials, as well as the preparation of otherwise inaccessible species. Pd-catalyzed coupling of aromatic dihalides to ortho-diaminoarenes furnishes embedded stable N,N'-dihydropyrazines expediently and in often excellent yields. The embedded N,N'-dihydropyrazines can then be oxidized by MnO2 to give substituted azatetracenes, azapentacenes, azahexacenes, and azaheptacenes, which are soluble, processable, and stable. This powerful Pd-catalyzed methodology allows the preparation of azaacenes, including diaza-, tetraaza- and hexaazaacenes. In combination with a suitable Pd precursor, Buchwald-type biarylphosphines have been shown to give excellent results. Activated dihalides such as 2,3-dihaloquinoxalines are coupled easily under simplified conditions, whereas 2,3-dibromoacenes require more stringent conditions and advanced catalyst precursors. Pd catalysts effect the assembly of azaacenes with otherwise difficult to obtain substitution patterns. High yields and flexibility make this method most attractive.

Effect of pore lengths on the reduction degree and lithium storage performance of Mesoporous SiOx nanomaterials

Mesoporous SiOx nanomaterials are regarded as promising lithium storage materials due to the unique architecture consisting of ultrasmall Si nanocrystals in mesoporous SiO2 matrix where the oxygen content plays a paramount role in the lithium storage performance. Different from previous works on the extrinsic reduction conditions of SiO2 precursors, this work investigates the effect of inner structures on the reduction degree and performances for the first time. Mesoporous SBA-15 rods with tunable pore lengths are prepared as precursors for SiOx. It is found that the O/Si atomic ratios decrease from 1.31 to 0.73 as the pore lengths reduce from 3 to 0.5 μm. With the shortest pore length, SiO0.73 nanorods exhibit the best lithium storage performance. Moreover, SiO0.73 nanorods are further modified by carbon nanolayers and present a remarkably improved performance (595 mAh g−1 after 60 cycles). This study can help us further understand the role of pore lengths on the reduction degree of SiO2 and enlighten us on adopting advanced SiO2 precursors with preferable inner structures.

Synthesis of an advanced precursor of Rivastigmine: Cinchona-derived quaternary ammonium salts as organocatalysts for stereoselective imine reductions

The enantioselective reduction of ketoimines has been successfully realized, using trichlorosilane as the stoichiometric reducing agent in the presence of catalytic amounts of a Lewis base, specifically a Cinchona derivative. For the first time, a novel class of derivatives was studied, featuring a picolinamide unit bound to the alkaloid scaffold, further functionalized as quaternary ammonium salt at the quinuclidine ring. Excellent yields and from good to high enantioselectivities (up to 92% ee) were obtained in the reduction of ketoimines. The novel catalysts were successfully employed in the synthesis of an enantiomerically pure advanced precursor of the blockbuster drug Rivastigmine.

Studies towards the synthesis of secoiridoids

A new approach to secoiridoids, based on the synthesis of the key functionalized intermediates 4 and 5, is presented. These compounds were tested in formal [3+3] cycloadditions. Acyl-chloride 15 was transformed into enol α,β-unsaturated ester 16, which was involved in a N-heterocyclic carbene rearrangement to give an advanced precursor 17 in the total synthesis of secoiridoids.

Highly Robust Advanced Single Precursor Based k 2.4 ILD for Beol Cu Interconnects

Continuous shrinking of the interconnect dimensions with each technology node requires reduction in RC (resistance-capacitance) delays. Reduction in capacitance requirement at 45nm node was met by introducing a k 2.4 inter-layer dielectric (ILD) at 2X metallization level [1]. However, the material was not readily extendable to next technology node because of the need for even higher modulus at the advanced nodes. Thus, there was a need to develop a new pSiCOH k 2.4 ILD with improved mechanical properties and damage susceptibility for back end of the line (BEOL) capacitance reduction. IBM/Alliance team has developed a number of pSiCOH films using a variety of precursors. Generally, the porous ultra-low k films are prepared by using a subtractive approach [2] in which the film is deposited using a mixture of skeleton and porogen precursor and then cured to remove the labile organic fraction [2]. An alternative to the above approach is to use a single precursor molecule consisting of skeleton with embedded porogen [3]. Developing a robust pSiCOH film with k < 2.55 has always been a challenge with this approach. This paper reports the development of a pSiCOH k 2.4 film deposited using a single precursor showing superior time dependent dielectric breakdown (TDDB) performance with lower integrated k (lower capacitance) as compared to the k 2.55 ILD pSiCOH film at 80 nm, 56 nm and 48 nm pitch. Octamethylcyclotetrasiloxane (OMCTS) precursor used for fabricating dense SiCOH dielectrics (k= 3.0-2.7) was used to form low k=2.4 film. The modified PECVD deposition conditions along with optimized UV cure resulted in k 2.4 ILD film deposited using a single precursor henceforth referred to as OMCTS Ex k 2.4. The new OMCTS Ex k 2.4 film has only slightly lower modulus as compared to the k 2.7 film deposited using OMCTS and O2 while showing comparable plasma induced damage (PID). PID was measured by thickness change after HF wet etch removed the damaged layer caused by standard plasma. In general, good TDDB performance is obtained by lowering porosity, increasing %C and reducing PID [4]. Each of these properties has been carefully optimized for new OMCTS Ex k 2.4 film by tuning the deposition and the UV cure conditions. Fig. 1 compares the RC performance for ULK k 2.55, ULK A k 2.4 (another PECVD k2.4 ILD) and OMCTS Ex k 2.4 film at 10 nm node. ULK A k 2.4 shows higher PID as compared to k 2.55 resulting in higher capacitance. In contrast, the OMCTS Ex k 2.4 retains the capacitance benefit because of the lower PID for this film. Table 1 compares the extracted k value for k 2.55 and the k 2.4 ILD’s at 80, 56 and 48 nm pitch. OMCTS Ex continues to show lower extracted k number with no significant increase in value with technology node scaling. Fig. 2 shows the TDDB performance of these ILD’s at 10 nm node. The higher carbon content with low plasma induced damage resulted in dramatically better TDDB for OMCTS Ex than other films. Important to note that the TDDB performance of this film is almost 15X better than the TDDB performance of k 2.55 and ULK A k 2.4 ILD. Conclusion A new advanced single precursor OMCTS Ex k 2.4 pSiCOH ILD film has been developed to meet the integration scaling and reliability requirements. The new OMCTS Ex k 2.4 film shows better film properties than the reference k 2.55 and other 2.4 films and retains capacitance benefit by demonstrating an overall lower integrated k value as compared to the k 2.55 ILD. Acknowledgement This work was performed by the Research and Development Alliance Teams at various IBM Research and Development Facilities.

C-glycosphingolipid precursors via iodocyclization of homoallyic trichloroacetimidates

The iodocyclization of homoallylic trichloroacetimidates derived from α-C-allyl galactoside were investigated. In line with the stereochemical trend observed for less substituted non-glycosylated frameworks, E and Z substrates delivered stereoselectively the 1,3-anti and 1,3-syn amino alcohol motifs, respectively. These products are advanced precursors to C-glycosides of the potent immunostimulatory glycolipid KRN7000.

The Advanced Lipoxidation end Product Precursor Malondialdehyde Induces IL-17E Expression and Skews Lymphocytes to the th17 Subset.

Malondialdehyde (MDA) is a highly reactive endogenous product of thromboxane synthesis in the prostagland and lipid peroxidation by reactive oxygen species. Elevated MDA levels occur in diabetes and atherosclerotic plaques. The aim of this study was to examine the molecular mechanisms of MDA-induced IL-17E cytokine expression and its effect on T-cell differentiation. Real-time PCR, RT-PCR and ELISA were used to assess the expression of IL-17 family cytokines in Jurkat T-cells and human peripheral blood lymphocytes (PBLCs) from diabetic subjects. Luciferase reporter assays were used for the promoter activation study. Pharmacological inhibitors were used for signaling pathway experiments. FACS analyses were used to measure the Th1, Th2 and Th17 subset levels. MDA induced significant (2- to 3-fold; p < 0.01) generation of IL-17E mRNA in a dose- and time-dependent manner in Jurkat T-cells and PBLCs. Elevated IL-17E mRNA levels were found in the lymphocytes from diabetic subjects. The increased IL-17E protein and mRNA levels correlate well with serum MDA levels from diabetic patients. Transient transfection of plasmid containing the minimum IL-17E promoter region (pIL-17E-Luc) showed a significant (2-fold; p < 0.01) increase in luciferase activity. Pretreatment of lymphocytes with pharmacological inhibitors showed the involvement of antioxidant, NF-ƙB, p38MAPK, PKC and ERK signaling pathways. Quantification of the Th1, Th2 and Th17 cell population in PBLCs via FACS analyses revealed an increase in the Th17 subset. These results show that MDA transcriptionally upregulates the expression of IL-17E in lymphocytes and alters lymphocyte differentiation towards the pathogenic Th17 subset.

A convenient chiron approach to (4R,5R)-5-hydroxyalkylbutan-4-olides and the corresponding 7-oxa analogues from d-(+)-mannitol via an advanced common precursor: syntheses of (−)-muricatacin, 7-oxa-(−)-muricatacin, (4R,5R)-(−)-5-hydroxy-4-decanolide, and (4R,5R)-(−)-7-oxa-5-hydroxy-4-dodecanolide

An efficient and concise chiron approach toward the synthesis of (−)-muricatacin and its unnatural 7-oxa analogue starting from commercially available and inexpensive d-(+)-mannitol via an advanced common chiral precursor has been described. In addition, (4R,5R)-(−)-5-hydroxy-4-decanolide and (4R,5R)-(−)-7-oxa-5-hydroxy-4-dodecanolide were also synthesized to show the versatility of this synthetic strategy. The methodology involves the conversion of a common chiral intermediate, prepared from d-(+)-mannitol in six steps, to a variety of target molecules in only two steps.

Mathematics growth trajectories in first grade: Cumulative vs. compensatory patterns and the role of number sense

We examined mathematics growth trajectories in first grade for overall achievement and three separate competences (Basic Precursors, Advanced Precursors, Computation). 153 German students computed seven web-based progress monitoring tests during the school year. Latent class growth analysis (LCGA) provided evidence for mainly cumulative patterns of performance development: In all competences, we found groups of initially high-performing students with the highest end scores and groups of initially low-performing students with little or no growth. In contrast to this general pattern, compensatory trajectories with groups of initially lower-performing students and steep growth were found. For precursor competences, these catch-up groups did not have increased odds of belonging to low-end outcome groups in higher competences. The findings demonstrate the added value of repeatedly assessing both precursor and grade-level skills for identifying students who follow favorable or unfavorable learning trajectories.

Engineering terpene biosynthesis in Streptomyces for production of the advanced biofuel precursor bisabolene.

The past decade has witnessed a large influx of research toward the creation of sustainable, biologically derived fuels. While significant effort has been exerted to improve production capacity in common hosts, such as Escherichia coli or Saccharomyces cerevisiae, studies concerning alternate microbes comparatively lag. In an effort to expand the breadth of characterized hosts for fuel production, we map the terpene biosynthetic pathway in a model actinobacterium, Streptomyces venezuelae, and further alter secondary metabolism to afford the advanced biofuel precursor bisabolene. Leveraging information gained from study of the native isoprenoid pathway, we were able to increase bisabolene titer nearly 5-fold over the base production strain, more than 2 orders of magnitude greater than the combined terpene yield in the wild-type host. We also explored production on carbon sources of varying complexity to, notably, define this host as one able to perform consolidated bioprocessing.

ChemInform Abstract: An Approach to the Carbon Backbone of Bielschowskysin. Part 1. Photocyclization Strategy.

Several macrocyclization reaction attempts of highly advanced precursors toward a total synthesis of marine diterpene bielschowskysin are disclosed. Biomimetic [2+2]-photocyclization reactions were applied to construct the cyclobutane core in these intermediates, which could be accessed along scalable high-yielding reaction sequences from cheap enantiopure starting-materials.

Bioproduction of baccatin III, an advanced precursor of paclitaxol, with transgenic Flammulina velutipes expressing the 10‐deacetylbaccatin III‐10‐O‐acetyl transferase gene

10-Deacetylbaccatin III (10-DAB) and baccatin III are intermediates in the biosynthesis of Taxol (an anti-cancer drug) and useful precursors for semi-synthesis of the drug. In this study, a bioconversion system was established for the production of baccatin III, an advanced precursor of paclitaxel, in the transgenic mushroom Flammulina velutipes expressing the 10-deacetylbaccatin III-10β-O-acetyltransferase gene. The expression vector pgFvs-TcDBAT containing the 10-deacetylbaccatin III-10β-O-acetyltransferase (DBAT) gene was constructed and transformed into the cells of F. velutipes by polyethylene glycol-mediated protoplast transformation. Polymerase chain reaction and Southern blotting analysis verified the successful integration of the exogenous DBAT gene into the genome of F. velutipes. Reverse transcription polymerase chain reaction and enzyme activity analyses confirmed that the DBAT gene was expressed in F. velutipes, and DBAT is able to convert substrate into baccatin III. The DBAT gene from the plant Taxus chinensis can be functionally expressed in F. velutipes. Transgenic F. velutipes expressing the DBAT gene is able to produce the target product, baccatin III. This is the first report about the transformation and expression of paclitaxel biosynthetic gene in the edible mushroom F. velutipes. This represents a significant step towards bio-production of paclitaxel and its advanced precursor baccatin III in an edible fungus.

Web-based progress monitoring in first grade mathematics

The purpose of our research was to examine a web-based tool for mathematics progress monitoring in first grade. The newly developed assessment tool uses several robust indicators and curriculum-based measures forming three competences (Basic Precursors, Advanced Precursors, and Computation) to determine comprehensive early numeracy skills in regular education. 373 students completed a total of eight online tests every two or three weeks. Results indicate that delayed alternate-form reliability was adequate (rM = .78). Repeated measures analyses with post hoc comparisons were used to ascertain the sensitivity to assess learning growth. All three competences showed linear growth rates that were significant over time, but only Computation and overall scores produced dependable increases from test to test. Predictive validity was determined using two standardised school achievement tests (end of first grade, end of second grade). Results indicate high predictive validity of the first four online tests (rM = .67, rM = .66 for 6 months and 18 months prediction). Correlations with teacher ratings of their students' skills confirmed this pattern. Results from student and teacher questionnaires indicate that the students were able to conduct the tests independently and that a three-week interval was adequate for regular‑education use. Teachers stated to use the progress monitoring results diversely for classroom purposes. We conclude that the use of a web-based assessment setting with diverse measures is beneficial with respect to psychometric properties and feasibility for frequent use in regular education.

Synthesis of isotopically labeled epothilones

The epothilones, including epothilones B and D, are macrocyclic lactones, which have potent cytotoxicities and promote the polymerization of tubulin to mictotubules by binding to and stabilizing the tubulin polymer. They have a very similar mechanism of action to paclitaxel (Taxol®). The determination of the microtubule-binding conformation of the epothilones is an important piece of information in designing improved analogs for possible clinical use, and internuclear distance information that will assist the determination of this conformation can be obtained by rotational echo double resonance (REDOR) NMR studies of microtubule-bound epothilones with appropriate stable isotope labels. Analogs of epothilone B and epothilone D with [(2) H3 ] and [(19) F] labels were prepared from an advanced precursor for potential use in REDOR NMR studies to determine internuclear distances in tubulin-bound ligand.

Enhanced Flux Pinning and Critical Current Density of $ \hbox{BaZrO}_{3}$-Doped $\hbox{Y}_{0.75} \hbox{Gd}_{0.25} \hbox{Ba}_{2} \hbox{Cu}_{3} \hbox{O}_{7-{\rm x}}$ Superconducting Films Prepared Using Advanced Low-Fluorine Solution

Y0.75 Gd0.25 Ba2 Cu3 O7- x (YGBCO) films with BaZrO3 (BZO) inclusions as pinning centers were prepared on LaAlO3 (00 l) substrates by metal-organic deposition via introducing zirconium (IV) acetylacetonate into the advanced low-fluorine YGBCO precursor solution. The BZO defects in the YGBCO film were found to induce the formation of a-oriented YGBCO grains on the film surface. An annealing process at a high temperature of 805 °C can completely eliminate the a-axis grains. The introduction of BZO defects in c-oriented YGBCO film can improve the film critical current density (Jc) and flux pinning of the films. Through the introduction of BZO nanostructure, the Jc of the YGBCO film processed at 805 °C was improved from 3 to 9 MA/cm2 at 77 K and 0 T. The flux pinning force density Fp also reached a high value of 38 GN/m3 at 65 K and 0.5-1 T.

Synthetic Studies towards an Advanced Precursor of the Jatrophane Diterpene Pl-4

Jatrophane diterpenes, isolated from members of the Euphorbiaceae­ plant family, constitute a class of biologically and structurally intriguing natural products. Herein, different strategies for the preparation of an advanced intermediate towards the total synthesis of the jatrophane diterpene Pl-4 are described. Key strategies for the elaboration of the jatrophane precursors include hydrometalation and radical reactions.

An Approach to the Carbon Backbone of Bielschowskysin, Part 1: Photocyclization Strategy

AbstractSeveral macrocyclization reaction attempts of highly advanced precursors toward a total synthesis of marine diterpene bielschowskysin are disclosed. Biomimetic [2+2]‐photocyclization reactions were applied to construct the cyclobutane core in these intermediates, which could be accessed along scalable high‐yielding reaction sequences from cheap enantiopure starting‐materials.