Sequential Conjugate Research Articles

Access to Tetrahydrothiopyrano[2,3‐b]Indole Derivatives via Zinc‐Catalyzed Asymmetric [3+3] Annulation of Indoline‐2‐Thiones with Yne–Enones

AbstractWe report herein an enantioselective [3+3] annulation of indoline‐2‐thiones with yne–enones by chiral dinuclear zinc catalysts via a Brønsted base and Lewis acid cooperative activation model. This transformation proceeded through sequential conjugate addition, allenyl ketone formation and intramolecular sulfa‐Michael 6‐endo‐trig cyclization. A range of enantioenriched tetrahydrothiopyrano[2,3‐b]indole derivatives bearing an exocyclic double bond were obtained in moderate yields with excellent stereoselectivities (up to 20 : 1 dr, 20:1 Z/E ratio and 95% ee). Late‐stage functionalization, large‐scale experiment and further derivatizations were also explored.

Design and Synthesis of Co-initiators via Base-Catalysed Sequential Conjugate Addition: Application in Photoinduced Radical Polymerisation Reaction.

Applications of photochemistry are becoming very popular in modern-day life due to its operational simplicity, environmentally friendly and economically sustainable nature in comparison to thermochemistry. In particular photoinduced radical polymerisation (PRP) reactions are finding more biological applications and especially in the areas of dental restoration processes, tissue engineering and artificial bone generation. A type-II photoinitiator and co-initiator-promoted PRP turned out to be a cost-effective protocol, and herein we report the design and synthesis of a new efficient co-initiator for a PRP reaction via a barrierless sequential conjugate addition reaction. Experimental mechanistic observations have been further complemented by computational data. Time for newly synthesised 1,2-benzenedithiol (DTH) based co-initiator promoted polymerisation of urethane dimethacrylate (UDMA, 70 %) and triethylene glycol dimethacrylate (TEGDMA, 30 %) in presence of 450 nm LED (15 W) under the aerobic conditions is 38 seconds. Polymeric material has high glass transition temperature, improved mechanical strength (860 BHN) and longer in-depth polymerisation (3 cm).

Rhodium(III)‐Catalyzed Dehydrogenative Annulation of 2‐Arylindazoles with Cyclic Enones

AbstractAn oxidative annulation of 2‐arylindazoles with cyclic enoneshas was developed using Rh(III)/Cu(OAc)2 catalytic system for the first time to produce 3,4‐dihydroindazolo[2,3‐f]phenanthridin‐1(2H)‐one derivatives in good yields with high selectivity. When AgSbF6 was used instead of Cu(OAc)2, the corresponding uncyclized products, 3‐(2‐(2H‐indazol‐2‐yl)phenyl)cyclohexan‐1‐one scaffolds were formed exclusively. The reaction proceeds through a sequential conjugate addition of ortho‐C–H bond of aryl group followed by an oxidative annulation of indazole ring to generate fused polycyclic scaffolds.

Stereoselective Synthesis of the I-L Fragment of the Pacific Ciguatoxins.

The I–L ring system found in all the Pacific ciguatoxins has been prepared from a tricyclic precursor in a highly stereoselective manner. Subtle differences in the reactivity of the enones present in the seven- and eight-membered rings of the tricyclic ether starting material have been exploited to allow selective protection of the enone in the eight-membered ring. Subsequent distereoselective allylation of the seven-membered ring has been accomplished by a palladium-mediated Tsuji-Trost reaction. The K-ring methyl and hydroxyl groups have been installed in a highly stereoselective manner by sequential conjugate reduction and enolate oxidation reactions. Ring L has been constructed by a use of a novel relay ring-closing metathesis reaction to complete the tetracyclic framework, which possesses the functionality necessary for elaboration of rings I and L and the introduction of ring M.

Improving vaccine administration in patients with solid malignancies in the outpatient setting.

194 Background: Pneumococcal and influenza vaccinations are recommended for all patients with any malignancy in accordance with the Infectious Disease Society of America. Patients undergoing chemotherapy for solid tumors have a 40-50 fold higher risk for the development of invasive pneumococcal disease compared to healthy adults with a case fatality rate of 35% and should receive the sequential 13-valent pneumococcal conjugate vaccine (PCV13) and 23-valent pneumococcal polysaccharide vaccine (PPSV23). In the outpatient setting, lack of provider knowledge, complexity of the pneumococcal vaccine regimen and disruption in work-flow of a busy clinic can lead to low rates of administration. Towards this end, we conducted a quality project to improve administration of both pneumococcal and influenza vaccines by at least 50% at one of our outpatient oncology clinics at Montefiore Medical Center in Bronx, NY during a 4 month period. Methods: We first provided provider and nursing education with regard to safety and efficacy of the vaccines in both the clinic as well as the infusion setting. Nurses were then prompted to screen patients and offer the vaccines during intake prior to all infusions and clinic visits. We created bulk orders which allowed nurses greater control of releasing vaccine orders previously entered by the director of the clinic. We also posted “cheat-sheets” on optimal timing, safety and sequence of administration of the vaccines in every patient room and nursing station. After our first cycle, we identified that there was a delay in work-flow in the outpatient clinic with delivery of the vaccines to the clinic from the pharmacy. We therefore obtained a secure vaccine fridge that was placed at the nursing station, which allowed nurses easy access to the vaccines. Results: When vaccine administration during the 2018-2019 influenza season was compared to the 2019-2020 influenza season, we found that these interventions improved the administration of the influenza vaccine by 70%. There was a dramatic increase in the number of PCV-13 vaccines administered by 350% (more than 5-fold) and increase in PPVS-23 by 12.5%. No immediate adverse reactions during this cycle were reported to our nurse manager. Conclusions: A simple intervention of improved work-flow of vaccine administration and increased education of providers and nurses translated to a dramatic improvement in the administration of influenza and PCV-13 vaccines in a busy outpatient oncology clinic.

A sequential conjugate gradient method to estimate heat flux for nonlinear inverse heat conduction problem

In this paper, a sequential conjugate gradient method is presented to reconstruct the undetermined surface heat flux for nonlinear inverse heat conduction problem (IHCP). This modified method combines the merits of sequential function specification method (SFSM) and conjugate gradient method (CGM). The proposed method can effectively eliminate the leading error which is inevitably generated in SFSM due to the existence of temporary assumption of the unknown parameters and reduce the computing time of nonlinear IHCP. The square wave and sine wave heat flux are used to evaluate the proposed method and the influence of the number of future time steps and measurement errors on the predicted results is studied. The numerical experiments verify the effectiveness and timeliness of the proposed nonlinear IHCP algorism in reconstructing the heat flux. The comparisons with the typical SFSM and CGM are conducted to demonstrate the superiority of the proposed method. The results show that proposed method is more accurate compared with that of the SFSM under the condition of large measurement errors and the computing time is much faster than that of CGM.

Receptor-Specific Delivery of Peptide Nucleic Acids Conjugated to Three Sequentially Linked N-Acetyl Galactosamine Moieties into Hepatocytes.

Peptide nucleic acids (PNAs) are DNA analogs that bind with high affinity to DNA and RNA in a sequence-specific manner but have poor cell permeability, limiting use as therapeutic agents. The work described here is motivated by recent reports of efficient gene silencing specifically in hepatocytes by small interfering RNAs conjugated to triantennary N-acetyl galactosamine (GalNAc), the ligand recognized by the asialoglycoprotein receptor (ASGPR). PNAs conjugated to either triantennary GalNAc at the N-terminus (the branched architecture) or monomeric GalNAc moieties anchored at Cγ of three consecutive PNA monomers of N-(2-aminoethyl)glycine (aeg) scaffolds (the sequential architecture) were synthesized on the solid phase. These formed duplexes with complementary DNA and RNA as shown by UV and circular dichroism spectroscopy. The fluorescently labeled analogs of GalNAc-conjugated PNAs were internalized by HepG2 cells that express the ASGPR but were not taken up by HEK-293 cells that lack this receptor. The sequential conjugate was internalized about 13-fold more efficiently than the branched conjugate into HepG2 cells, as demonstrated by confocal microscopy. The results presented here highlight the potential significance of the architecture of GalNAc conjugation for efficient uptake by target liver cells and indicate that GalNAc-conjugated PNAs have possible therapeutic applications.

Enhanced parallelization of the incremental 4D‐Var data assimilation algorithm using the Randomized Incremental Optimal Technique

AbstractIncremental 4D‐Var is a data assimilation algorithm used routinely at operational numerical weather prediction (NWP) centres worldwide. The algorithm solves a series of quadratic minimization problems (inner‐loops) obtained from linear approximations of the forward model around nonlinear trajectories (outer‐loops). Since most of the computational burden is associated with the inner‐loops, many studies have focused on developing computationally efficient algorithms to solve the least‐square quadratic minimization problem, in particular through time parallelization. This paper presents the first implementation and testing of a recently proposed method for parallelizing incremental 4D‐Var, the Randomized Incremental Optimal Technique (RIOT), which replaces the traditional sequential conjugate gradient (CG) iterations in the inner‐loop of the minimization with fully parallel randomized singular value decomposition (RSVD) of the preconditioned Hessian of the cost function. RIOT is tested using the standard Lorenz‐96 model (L‐96) as well as two realistic high‐dimensional atmospheric source inversion problems based on aircraft observations of black carbon concentrations. A new outer‐loop preconditioning technique tailored to RSVD was introduced to improve convergence stability and performance. Results obtained with the L‐96 system show that the performance improvement from RIOT compared to standard CG algorithms increases significantly with nonlinearities. Overall, in the realistic black carbon source inversion experiments, RIOT reduces the wall‐clock time of the 4D‐Var minimization by a factor of 2 to 3, at the cost of a factor of 4 to 10 increase in energy cost due to the large number of parallel cores used. Furthermore, RIOT enables reduction of the wall‐clock time computation of the analysis‐error covariance matrix by a factor of 40 compared to a standard iterative Lanczos approach. Finally, as evidenced in this study, implementation of RIOT in an operational NWP system will require a better understanding of its convergence properties as a function of the Hessian characteristics and, in particular, the degree of freedom for signal of the inverse problem.

Divergence of polycondensation by a tandem reaction based on sequential conjugate substitutions

Polycondensation, which was based on sequential conjugate substitution (SN2′) reactions of β-bromo-α-(bromomethyl)acrylates and dithiol, afforded diverse structures of polysulfides with exo- and endo-olefin units.

Rh(III)-Catalyzed Tandem Bicyclization of 2-Arylimidazo[1,2-a]pyridines with Cyclic Enones for the Construction of Bridged Scaffolds.

An efficient Rh(III)-catalyzed bicyclization of 2-arylimidazo[1,2-a]pyridine with cyclic enones has been developed for the synthesis of bridged imidazopyridine derivatives in excellent yields up to 95%. The reaction proceeds through a sequential conjugate addition of ortho-C-H bond of aryl group followed by an intramolecular C3-alkylation of imidazopyridine ring in a highly regioselective manner.

Lewis Acid Promoted Trapping of Chiral Aza-enolates

We present a study on sequential conjugate addition of ­Grignard reagents to alkenyl-heteroarenes followed by trapping of the resulting enolates, yielding moderate to good diastereoselectivities. Contrary to conventional wisdom, one-pot conjugate addition/trapping using two reactive Michael acceptors in combination with Grignard reagents can proceed via conjugate addition to the least reactive Michael acceptor. This unusual chemoselectivity is triggered by the presence of a Lewis acid, reverting the usual reactivity order of Michael acceptors.

A [4 + 3] Annulation Reaction of aza- o-Quinone Methides with Arylcarbohydrazonoyl Chlorides for Synthesis of 2,3-Dihydro-1 H-benzo[ e][1,2,4]triazepines.

An unprecedented [4 + 3] annulation reaction of aza- ortho-quinone methides with arylcarbohydrazonoyl chlorides has been achieved under mild conditions. The annulation underwent a sequential conjugate addition/intramolecular annulation/rearrangement, providing a useful method for the synthesis of biologically interesting 2,3-dihydro-1 H-benzo[ e][1,2,4]triazepine.

Organocascade Synthesis of Annulated (Z)-2-Methylenepyrans: Nucleophilic Conjugate Addition of Hydroxycoumarins and Pyranone to Branched Nitro Enynes via Allene Formation/Oxa-Michael Cyclization/Alkene Isomerization Sequence.

An efficient organocatalytic reaction using 1,3-nitro enynes with 4-hydroxycoumarin and 4-hydroxy-6-methyl-2-pyrone to afford pyrano-annulated scaffolds in high yield (up to 88% yield) and excellent stereoselectivities (up to >20:1 dr and >99% ee) is described. The reaction proceeded through sequential conjugate addition, allene formation, intramolecular oxa-Michael 6-endo-dig cyclization and DABCO-catalyzed olefin isomerization. A kinetic profile for isomerization was established. The mechanism for the organocascade reaction was proposed according to requisite computational and mechanistic experimental studies.

Direct Minimization for Ensemble Electronic Structure Calculations

We consider a direct optimization approach for ensemble density functional theory electronic structure calculations. The update operator for the electronic orbitals takes the structure of the Stiefel manifold into account and we present an optimization scheme for the occupation numbers that ensures that the constraints remain satisfied. We also compare sequential and simultaneous quasi-Newton and nonlinear conjugate gradient optimization procedures, and demonstrate that simultaneous optimization of the electronic orbitals and occupation numbers improve performance compared to the sequential approach.

Deep-seated fragmentation, transport of breccia dikes and emplacement: An example from the Borborema province, northeastern Brazil

Three syenite dike sets, named the Santa Cruz dikes, are coeval with the 627 ± 13 Ma old porphyritic calc-alkalic Princesa Izabel granitoid, northeastern Brazil. Dike set 1 is up to 1.5 m wide, strike 030–040 Az, roughly parallel to the regional foliation. Dike set 2 strikes 120°–130 Az and consists of xenolith-bearing syenites and is roughly parallel to dike set 3, which is up to 1.5 m wide and consists of xenolith-rich syenites forming matrix-supported breccias. Xenoliths in dike sets 2 and 3 are usually up to 3 cm long, angular to sub-rounded, tend to be evenly distributed and occupy ∼50% of the volume of dike set 3. They are amphibolite, mica-pyroxenite and diorite from deep source, and gneiss and feldspar xenocrysts from the conduit. The large amount of dense ultramafic/mafic xenoliths in the breccia dikes indicates rapid ascent of the host magma. The calculated natural viscosity, based on whole-rock chemical data, is 680–4600 Pa.s for 2.3 wt% water and temperatures from 1000 to 900 °C, respectively. A minimum ascent rate of ∼0.3 m/s is estimated from the settling velocity of a 30 cm-long diorite xenolith, the largest one, and an initial fraction of xenoliths of 5%. Progressive addition of xenoliths to the magma during its ascent increased the viscosity of the liquid–solid mixture during emplacement, and this would imply a Bingham rather than Newtonian behavior. These xenoliths were formed by early fracturing of wall rocks during dike propagation associated with thermal spalling of the wall rocks, by intrusion of magma along dike-parallel fractures during the development of a sequential conjugate pair of shear zones. Xenoliths are abundant not only because these magmas have ascended rapidly and could transport them, but also because the initial low viscosity of the magma promoted intense fracturing of the conduit.

ChemInform Abstract: Organocatalytic Asymmetric One‐Pot Sequential Conjugate Addition/Dearomative Fluorination: Synthesis of Chiral Fluorinated Isoxazol‐5(4H)‐ones.

AbstractBy using the bifunctional chiral tertiary amino‐thiourea catalyst STC, a series of chiral fluorinated isoxazol‐5(4H)‐ones containing a fluorine‐substituted quarternary stereocenter are obtained in high yields with high enantio‐ and diastereoselectivities.

Truss Structural Optimization Based on Globally Convergent Version of MMA

The subproblem of the globally convergent version of method of moving asymptotes (GCMMA) was deeply studied and realized by Lagrange dual method, sequential unconstrained minimization technique (SUMT) and conjugate gradient method. Based on the convex, separable and conservative properties of subproblem, a dual problem was built by using Lagrange dual method. The dual problem was transformed into unconstrained optimization problem using SUMT and solved by conjugate gradient method. Finally, the feasibility of solution of subproblem is demonstrated by truss structural optimization problem. Comparing with other optimization algorithms, GCMMA can converge to the global optimal solution.

Organocatalytic Asymmetric One-Pot Sequential Conjugate Addition/Dearomative Fluorination: Synthesis of Chiral Fluorinated Isoxazol-5(4H)-ones

A facile one-pot sequential conjugate addition/dearomative fluorination transformation of isoxazol-5(4H)-ones with nitroolefins and N-fluorobenzenesulfonimide (NFSI) has been developed. By using a bifunctional chiral tertiary amino-thiourea catalyst, a series of chiral fluorinated isoxazol-5(4H)-ones containing one fluorine-substituted quarternary stereocenter were obtained in high yields with high enantio- and diastereoselectivities. Further transformation of adducts could afford isoxazolidin-5-one derivatives with three contiguous stereocenters.

ChemInform Abstract: Electrochemically Initiated Tandem and Sequential Conjugate Addition Processes: One‐Pot Synthesis of Diverse Functionalized Isoindolinones.

AbstractSynthesis of highly functionalized 3‐isoindolinones is achieved by the present new electroreductively‐catalyzed reaction of 1,3‐dicarbonyl compounds with cyanobenzaldehyde (I).

Electrochemically Initiated Tandem and Sequential Conjugate Addition Processes: One‐Pot Synthesis of Diverse Functionalized Isoindolinones

AbstractA tandem aldol–heterocyclization–rearrangement reaction and one‐pot sequential Michael addition allowed a direct access to highly functionalized 3‐isoindolinones containing quaternary carbon centers. The desired products are obtained under mild conditions and in short reaction times by galvanostatic electrolysis in a divided cell. A further tandem intramolecular heterocyclization reaction leading to synthetically relevant hemiaminal derivatives has been established with suitable Michael acceptors.