Iterative Synthesis Research Articles

Iterative synthesis of 1,3-polyboronic esters with high stereocontrol and application to the synthesis of bahamaolide A.

Polyketide natural products often contain common repeat motifs, for example, propionate, acetate and deoxypropionate, and so can be synthesized by iterative processes. We report here a highly efficient iterative strategy for the synthesis of polyacetates based on boronic ester homologation that does not require functional group manipulation between iterations. This process involves sequential asymmetric diboration of a terminal alkene, forming a 1,2-bis(boronic ester), followed by regio- and stereoselective homologation of the primary boronic ester with a butenyl metallated carbenoid to generate a 1,3-bis(boronic ester). Each transformation independently controls the stereochemical configuration, making the process highly versatile, and the sequence can be iterated prior to stereospecific oxidation of the 1,3-polyboronic ester to yield the 1,3-polyol. This methodology has been applied to a 14-step synthesis of the oxopolyene macrolide bahamaolide A, and the versatility of the 1,3-polyboronic esters has been demonstrated in various stereospecific transformations, leading to polyalkenes, -alkynes, -ketones and -aromatics with full stereocontrol.

One-pot approach for multi-step, iterative synthesis of sequence-defined oligocarbamates

High-yielding and scalable methods for iterative synthesis of sequence-defined macromolecules are a great challenge in modern polymer chemistry. Sequence-defined macromolecules are fabricated by multi-step iterative processes that involve high reagent and solvent consumption. Moreover, every consecutive step causes yield losses that result in low overall yield. Despite the envisioned valuable functions and applications of sequence-defined polymers, the synthetic limitations constitute a barrier for the exploitation of their practical potential. Here, we investigated the one-pot synthesis of oligocarbamates without the purification of intermediates. To control the monomer sequence without isolation of intermediate product at every step, we introduced a monitoring feedback loop to fuel the exact amount of reagents to the reaction mixture, assuring full conversion of each reaction. Based on a one-pot strategy, we have developed a facile approach for the preparation of uniform oligocarbamates with full control of monomer order and defined stereochemistry. The great advantage of the presented methodology is the scalability of the process (demonstrated for synthesis of 50 g) and high yield (up to 95%). Oligomers obtained on a large scale can be further used as precursors for the synthesis of polymers with high molar mass. One-pot methods combined with chemoselective reactions bear the potential to overcome existing synthesis limitations and unlock the practical use of sequence-defined macromolecules. The presented concept might be further extended to different multi-step processes.

Photo‐Induced Homologation of Carbonyl Compounds for Iterative Syntheses

AbstractWe describe a photo‐induced reaction for the in situ generation of highly reactive alkyl diazo species from carbonyl precursors via photo‐excitation of N‐tosylhydrazone anions. The diazo intermediates undergo efficient C−H insertion of aldehydes, leading to the productive synthesis of aldehydes and ketones. The method is applicable to the iterative synthesis of densely functionalized carbonyl compounds through sequential trapping of the diazo species with various aldehydes. The reaction proceeds without the need of any catalyst by light irradiation and features high functional group tolerance. More than 70 examples, some performed on a gram‐scale, demonstrate the broad applicability of this reaction sequence in synthesis.

Photo-Induced Homologation of Carbonyl Compounds for Iterative Syntheses.

We describe a photo-induced reaction for the in situ generation of highly reactive alkyl diazo species from carbonyl precursors via photo-excitation of N-tosylhydrazone anions. The diazo intermediates undergo efficient C-H insertion of aldehydes, leading to the productive synthesis of aldehydes and ketones. The method is applicable to the iterative synthesis of densely functionalized carbonyl compounds through sequential trapping of the diazo species with various aldehydes. The reaction proceeds without the need of any catalyst by light irradiation and features high functional group tolerance. More than 70 examples, some performed on a gram-scale, demonstrate the broad applicability of this reaction sequence in synthesis.

Optimized design of block copolymers with covarying properties for nanolithography.

The ability to impart multiple covarying properties into a single material represents a grand challenge in manufacturing. In the design of block copolymers (BCPs) for directed self-assembly and nanolithography, materials often balance orthogonal properties to meet constraints related to processing, structure and defectivity. Although iterative synthesis strategies deliver BCPs with attractive properties, identifying materials with all the required attributes has been difficult. Here we report a high-throughput synthesis and characterization platform for the discovery and optimization of BCPs with A-block-(B-random-C) architectures for lithographic patterning in semiconductor manufacturing. Starting from a parent BCP and using thiol-epoxy 'click' chemistry, we synthesize a library of BCPs that cover a large and complex parameter space. This allows us to readily identify feature-size-dependent BCP chemistries for 8-20-nm-pitch patterns. These blocks have similar surface energies for directed self-assembly, and control over the segregation strength to optimize the structure (favoured at higher segregation strengths) and defectivity (favoured at lower segregation strengths).

Iterative Synthesis of Inulin-Type Fructooligosaccharides Enabled by Stereoselective β-d-Fructofuranosylation.

Inulin-type fructooligosaccharides (FOSs) constitute an abundant subgroup of fructans with important biological activities. However, the availability of individual fructooligosaccharides with an accurate structure in high purity and quality remains challenging. We herein report the first iterative synthesis of five inulin-type FOSs with degrees of polymerization ranging from 3 to 7 via highly stereoselective β-(2 → 1)-d-fructofuranosylation on a gram scale. Central to the synthesis is the decisive use of the 1-O-TIPS-6-O-picoloyl-protected fructofuranosyl thioglycoside donor, which assured the excellent β-selective glycosylation by the hydrogen-bond-mediated aglycone delivery (HAD).

Iterative synthesis, structures, and properties of acyclic and cyclic acridone oligomers

AbstractAcyclic and cyclic acridone‐2,7‐diyl oligomers were synthesized by an iterative procedure from 10‐mesitylacridone as heteroatom containing π‐conjugated compounds. The oligomeric chain was elongated by a combination of regioselective bromination, borylation, Ni(0)‐mediated homocoupling, and Suzuki‐Miyaura coupling up to acyclic hexamer. Subsequently, the cyclic hexamer was synthesized by the bromination and intramolecular coupling of the acyclic hexamer. The DFT calculations revealed that the acyclic oligomers preferred to take extended structures with anti conformations, whereas the cyclic hexamer took a macrocyclic structure with syn conformations. The UV/Vis and fluorescence spectra of the series of oligomers were measured, and the effects of the chain length and the cyclization are discussed in terms of π‐conjugation.

Utilization of Function Generation Synthesis on Biomimetics: A Case Study on Moray Eel Double Jaw Design.

Throughout history, humans have observed living or non-living things in nature and then imitated them in relation to these observations. This is due to the fact that the energy found in nature is generally consumed at an optimal level in order for it to endure. Biomimetic inspiration in many designs and applications is widely displayed, including within the field of engineering. In this paper, we were inspired by the double set of jaws found in the moray eel, which gives this fish a huge advantage while hunting, with a mobile pharyngeal jaw that works together with its oral jaw in order to overcome ineffective suction capabilities. A procedure that mimics the hunting motion of the moray eel was utilized by considering the overall movement as a single degree of freedom with multiple outputs on account of the repeating motion that is required during hunting. This procedure includes structural and dimensioning synthesis, wherein the latter was utilized with analytic kinematic synthesis for each linkage transfer. The flexibilities in parameters were taken into account with a novel multiple iterative kinematic synthesis algorithm that resulted in various mechanisms with the same purpose. Among the excessive number of resultant mechanisms, the optimization was carried out by considering the highest torque transmission ratio at critical timings that were specified as bio-constraints. In the end, the kinematic movement validation was utilized.

Youth Positive Mental Health Concepts and Definitions: A Systematic Review and Qualitative Synthesis.

Background: Research on youth positive mental health (PMH) lacks comprehensiveness. We reviewed literature to (i) identify and understand concepts related to youth PMH and (ii) to summarize their definitions under broad conceptual themes. Method: We conducted a systematic review using PRISMA methodology. The protocol was registered in PROSPERO database (ID:CRD42020203712). Pubmed, Embase, PsycINFO, and OpenGrey databases were searched for publications that examined, assessed, explained, or defined PMH concepts in youth populations. Methods included searching, independent screening and review using pre-determined inclusion and exclusion criteria, extraction, coding, and iterative thematic syntheses of literature. Results: Of 3427 unique records identified, 105 articles from 26 countries met review criteria. Qualitative analysis resulted in 22 broad themes of youth PMH. These included interpersonal relationships (interpersonal competence, school connectedness, etc.), positive emotions (feel and create pleasant emotions, gratitude, etc.), self-efficacy (strengths, human agency, etc.), life satisfaction (global assessment of one’s life), and personal growth (goal achievement, life aspirations, etc.). Five novel concepts related to youth PMH were identified. Conclusions: Our review summarized and operationalized multiple concepts of youth PMH for applications in research, evaluation, and public health improvement.

Programmable Fabrication of Monodisperse Graphene Nanoribbons via Deterministic Iterative Synthesis.

While enormous progress has been achieved in synthesizing atomically precise graphene nanoribbons (GNRs), the preparation of GNRs with a fully predetermined length and monomer sequence remains an unmet challenge. Here, we report a fabrication method that provides access to structurally diverse and monodisperse "designer" GNRs through utilization of an iterative synthesis strategy, in which a single monomer is incorporated into an oligomer chain during each chemical cycle. Surface-assisted cyclodehydrogenation is subsequently employed to generate the final nanoribbons, and bond-resolved scanning tunneling microscopy is utilized to characterize them.

Factors influencing appropriate use of interventions for management of women experiencing preterm birth: A mixed-methods systematic review and narrative synthesis.

Preterm birth-related complications are the leading cause of death in newborns and children under 5. Health outcomes of preterm newborns can be improved with appropriate use of antenatal corticosteroids (ACSs) to promote fetal lung maturity, tocolytics to delay birth, magnesium sulphate for fetal neuroprotection, and antibiotics for preterm prelabour rupture of membranes. However, there are wide disparities in the rate and consistency in the use of these interventions across settings, which may underlie the differential health outcomes among preterm newborns. We aimed to assess factors (barriers and facilitators) affecting the appropriate use of ACS, tocolytics, magnesium sulphate, and antibiotics to improve preterm birth management. We conducted a mixed-methods systematic review including primary qualitative, quantitative, and mixed-methods studies. We searched MEDLINE, EMBASE, CINAHL, Global Health, and grey literature from inception to 16 May 2022. Eligible studies explored perspectives of women, partners, or community members who experienced preterm birth or were at risk of preterm birth and/or received any of the 4 interventions, health workers providing maternity and newborn care, and other stakeholders involved in maternal care (e.g., facility managers, policymakers). We used an iterative narrative synthesis approach to analysis, assessed methodological limitations using the Mixed Methods Appraisal Tool, and assessed confidence in each qualitative review finding using the GRADE-CERQual approach. Behaviour change models (Theoretical Domains Framework; Capability, Opportunity, and Motivation (COM-B)) were used to map barriers and facilitators affecting appropriate use of these interventions. We included 46 studies from 32 countries, describing factors affecting use of ACS (32/46 studies), tocolytics (13/46 studies), magnesium sulphate (9/46 studies), and antibiotics (5/46 studies). We identified a range of barriers influencing appropriate use of the 4 interventions globally, which include the following: inaccurate gestational age assessment, inconsistent guidelines, varied knowledge, perceived risks and benefits, perceived uncertainties and constraints in administration, confusion around prescribing and administering authority, and inadequate stock, human resources, and labour and newborn care. Women reported hesitancy in accepting interventions, as they typically learned about them during emergencies. Most included studies were from high-income countries (37/46 studies), which may affect the transferability of these findings to low- or middle-income settings. In this study, we identified critical factors affecting implementation of 4 interventions to improve preterm birth management globally. Policymakers and implementers can consider these barriers and facilitators when formulating policies and planning implementation or scale-up of these interventions. Study findings can inform clinical preterm birth guidelines and implementation to ensure that barriers are addressed, and enablers are reinforced to ensure these interventions are widely available and appropriately used globally.

Iterative Synthesis of Contorted Macromolecular Ladders for Fast-Charging and Long-Life Lithium Batteries.

We report here an iterative synthesis of long helical perylene diimide (hPDI[n]) nanoribbons with a length up to 16 fused benzene rings. These contorted, ladder-type conjugated, and atomically precise nanoribbons show great potential as organic fast-charging and long-lifetime battery cathodes. By tuning the length of the hPDI[n] oligomers, we can simultaneously modulate the electrical conductivity and ionic diffusivity of the material. The length of the ladders adjusts both the conjugation for electron transport and the contortion for lithium-ion transport. The longest oligomer, hPDI[6], when fabricated as the cathode in lithium batteries, features both high electrical conductivity and high ionic diffusivity. This electrode material exhibits a high power density and can be charged in less than 1 min to 66% of its maximum capacity. Remarkably, this material also has exceptional cycling stability and can operate for up to 10,000 charging-discharging cycles without any appreciable capacity decay. The design principles described here chart a clear path for organic battery electrodes that are sustainable, fast-charging, and long lasting.

4-Alkynoic Acids in the Synthesis of Biologically Important Porphyrinoids

In this talk an account is given of the author's use of 4-alkynoic acid derivatives in the synthesis of members of the chlorin, bacteriochlorin and corrin classes of macrocyclic tetrapyrroles. In the case of chlorins, we employed a novel "2+2" condensation to prepare both C,D-symmetric and non-symmetric chlorins, made possible by the ready availability of highly substituted semicorrins derived from 4-alkynoic acids. Alkyne acids also played a prominent role in a new 16p-electrocyclization route to bacteriochlorins, and in iterative syntheses of semicorrins and secocorrins related to vitamin B12. Finally, we describe enantioselective syntheses of ring-C and ring-D alkyne acids for a proposed synthesis of cobyric acid. Figure 1

4th generation nonsteroidal aromatase inhibitors: An iterative SAR-guided design, synthesis, and biological evaluation towards picomolar dual binding inhibitors

One in every eight women will be diagnosed with breast cancer during their lifetime and approximately 70% of all patients are oestrogen receptor (ER) positive depending upon oestrogen for their growth accounting for third generation aromatase (CYP19A1) inhibitors being the mainstay in the treatment of ER-positive breast cancer. Despite the success of current aromatase inhibitors, acquired resistance occurs after prolonged therapy. Although the precise mechanisms of resistance are not known, lack of cross resistance among aromatase inhibitors drives the need for a newer generation of inhibitors to overcome this resistance alongside minimising toxicity and adverse effects. Novel triazole-based inhibitors were designed based on previously published parent compound 5a, making use of the now available crystal structure of CYP19A1 (PDB 3S79), to make modifications at specific sites to explore the potential of dual binding at both the active site and the access channel. Modifications included adding long chain substituents e.g. but-2-ynyloxy and pent-2-ynyloxy at different positions including the most active compound 13h with IC50 value in the low picomolar range (0.09 nM). Aromatase inhibition results paired with molecular dynamics studies provided a clear structure activity relationship and favourable dual binding mode was verified. Toxicity assays and CYP selectivity profile studies for some example compounds were performed to assess the safety profile of the prepared inhibitors providing the basis for the 4th generation nonsteroidal aromatase inhibitors.

MO040: Development of BBP-711, a small molecule inhibitor of glycolate oxidase for primary hyperoxaluria type 1 and recurrent kidney stone formers

Abstract BACKGROUND AND AIMS BBP-711 is an investigational small molecule inhibitor of glycolate oxidase (GO), currently in development for the treatment of primary hyperoxaluria type 1 (PH1) and recurrent nephrolithiasis. Selection of BBP-711 as a drug candidate followed structural activity optimization and a pharmacological testing strategy that included functional activity in enzyme assays, target engagement in cellular assays and efficacy studies in a rodent model (Agxt−/− mice) of primary hyperoxaluria type 1. METHOD BBP-711 was developed by iterative synthesis and study of the structure–activity relationship of more than 50 GO inhibitors. Lead molecules including BBP-711 were assessed for functional activity by determining inhibition of the conversion of glycolate to oxalate with purified human, mouse and rat HAOX1 enzymes. The ability of BBP-711 to bind directly to immobilized purified hGO (HAOX1 gene product) was evaluated by surface plasmon resonance. Selectivity of BBP-711 was assessed by determining its inhibition of several physiologically related gene products including that from HAOX2. In vitro efficacy of BBP-711 was tested via inhibition of oxalate production in primary hepatocytes cultured from hyperoxaluric Agxt−/− mice. In vivo efficacy of BBP-711 on urinary oxalate excretion was assessed at various doses given by oral gavage in Agxt −/− mice. Pharmacokinetics of BBP-711 was investigated to assess plasma and liver concentrations associated with efficacy. RESULTS BBP-711 is a potent inhibitor of human, rat and mouse GO (IC50 = 15.4 nM, 22.4 nM and 149 nM, respectively). BBP-711 demonstrated stronger direct binding to hGO1 (KD = 6.31 nM) than to rGO2 (KD = 12.8 nM), indicating its preference for GO1 as a target. BBP-711 specificity was demonstrated with <10% activity against off-target enzymes D-amino acid oxidase, dihydroorotate dehydrogenase and lactate dehydrogenase-A at 10 µM. BBP-711 demonstrated concentration-dependent inhibition of oxalate production by Agxt−/− hepatocytes (IC50 = 24.2 nM at 24 hours, IC50 = 42.9 nM at 48 hours). When orally dosed at 7 mg/kg for 5 days in Agxt−/− mice, BBP-711 produced a maximum reduction of urinary oxalate (60%) as well as maximum inhibition of GO activity (>88%). Higher doses did not result in greater reduction in urinary oxalate. Liver exposures (AUC0-24hr) were higher than plasma exposures at all doses tested. GO engagement by BBP-711 was also assessed in an ex vivo assay. Liver extracts from Agxt−/− and wild-type mice dosed with BBP-711 show a dose-dependent reduction in ex vivo GO activity at 1 and 4-hour post-dose. CONCLUSION Iterative and rational optimization of small molecule GO inhibitors resulted in BBP-711, a potent and specific inhibitor of GO with drug-like properties.

Peptidic Scaffolds Enable Rapid and Multivariate Secondary Sphere Evolution for an Abiotic Metallocatalyst

Metalloenzymes have benefited from the iterative process of evolution to achieve the precise arrangements of secondary sphere non-covalent interactions that enhance metal-centered catalysis. Iterative synthesis of scaffolds that display complex secondary sphere elements in abiotic systems can be highly challenging and time-intensive. To overcome this synthetic bottleneck, we developed a highly modular and rapid synthetic strategy, leveraging the efficiency of solid-phase peptide synthesis and conformational control afforded by non-canonical residues to construct a ligand platform displaying up to four unique residues of varying electronics and sterics in the secondary coordination sphere. As a proof-of-concept that peptidic secondary sphere can cooperate with the metal complex, we applied this scaffold to a well-known, modestly active C-H oxidizing Fe catalyst to evolve specific non-covalent interactions that is more than double its catalytic activity. Solution-state NMR structures of several catalyst variants suggest that higher activity is correlated with a hydrophobic pocket above the Fe center that may enhance the formation of a catalyst-substrate complex. Above all, we show that peptides are a convenient, highly modular, and structurally defined ligand platform for creating secondary coordination spheres that comprise multiple, diverse functional groups.

Inside Cover: Iterative Synthesis of 2‐Deoxyoligosaccharides Enabled by Stereoselective Visible‐Light‐Promoted Glycosylation (Angew. Chem. Int. Ed. 20/2022)

A visible-light-promoted iterative synthesis of 2-deoxyoligosaccharides is reported by De-Cai Xiong, Xin-Shan Ye, and co-workers in their Research Article (e202114726). The rapid constructions of oligosaccharides, 20-mer deoxyglycan, and digoxin are facilitated by a bromide-based hydrogen species through an electron transfer process.

Innentitelbild: Iterative Synthesis of 2‐Deoxyoligosaccharides Enabled by Stereoselective Visible‐Light‐Promoted Glycosylation (Angew. Chem. 20/2022)

Sichtbares Licht vermittelt die iterative Synthese von 2-Desoxyoligosacchariden, über die De-Cai Xiong, Xin-Shan Ye und Mitarbeiter in ihrem Forschungsartikel berichten (e202114726). Der schnelle Aufbau von Oligosacchariden, 20-mer-Desoxyglycan und Digoxin gelingt in Gegenwart einer Wasserstoffspezies auf Bromidbasis über einen Elektronentransferprozess.

Participatory design application in obesity prevention targeting young adults and adolescents: a mixed-methods systematic scoping review protocol

BackgroundPrevention of obesity is economically and sociologically preferable to treatment, with early intervention key to preventing excess weight gain and obesity. The transition from adolescence to young adulthood is a critical intervention period. An expert-led, top-down model has dominated obesity prevention research and practice with limited success. Participatory design (PD) offers potential in transforming obesity prevention research and practice by delivering bottom-up solutions that young people value and may therefore voluntarily engage with over time. An evidence synthesis of PD application in obesity prevention targeting adolescents and young adults is currently lacking.ObjectivesReport the protocol for a mixed-methods systematic scoping review which aims to integrate and synthesise available evidence on PD application in obesity prevention targeting adolescents and young adults. Specifically, the review will address three research questions:RQ1: How is PD defined in obesity prevention interventions targeting adolescents and young adults?RQ2: To what extent is PD applied in obesity preventions interventions targeting adolescents and young adults?RQ3a: How is the utility of PD evaluated in obesity preventions interventions targeting adolescents and young adults?RQ3b: What is the utility of PD application in obesity prevention interventions targeting adolescents and young adults?MethodsThis mixed-methods systematic scoping review protocol adheres to the PRISMA-P guidelines and is informed by the PRISMA extension for scoping reviews (PRISMA-ScR). The search strategy and eligibility criteria are informed by the sample, phenomenon of interest, design, evaluation, and research type tool. Eligible studies will be peer-reviewed literature published in English, reporting on PD application in obesity prevention interventions (including intervention development, implementation, and/or evaluation) targeting adolescents and young adults (aged 10–35 years). Study designs will include qualitative, quantitative, and mixed methods. The review will comprise a systematic literature search, eligibility screening, data extraction, quality assessment using the Mixed-Methods Appraisal Tool (MMAT), and data analysis using an iterative narrative evidence synthesis approach. Evidence on PD application will be thematically integrated in terms of who was involved, when they were involved, and how and why they were involved. Further thematic analyses will be conducted according to the MATE taxonomy and the United Kingdom Medical Research Council (UK MRC’s) key functions of process evaluations. The MATE taxonomy classifies PD application in terms of methodology, agent of change, training, and engagement. The MRC describes three functions of process evaluations: implementation, mechanisms of impact, and context. Applying both in the evidence synthesis is intended to provide a more complete picture of PD application. Exploratory analyses will be conducted to assess any potential associations between PD application and effectiveness across key outcomes (weight, physical activity, sedentary time, nutrition and dietary habit, mental health, and sleep) reported within intervention evaluations.ConclusionsElucidating PD application is a prerequisite to establishing its utility. Through the location and synthesis of available evidence on PD application in obesity prevention targeting adolescents and young adults, this review will categorise and describe different methods of PD application and explore the utility of PD application including whether any differences may be observed between PD method applied and the effectiveness of obesity prevention interventions. Implications will be delineated from the narrative evidence synthesis to inform future research and advance practice in this context.Systematic review registrationPROSPERO CRD42021268240

High-precision vapor pressure measurement apparatus with facile and inexpensive construction

This study describes an apparatus for high-precision variable temperature measurement of liquid vapor pressure. The apparatus can be used to measure the vapor pressure using only 0.5 ml of the liquid sample. To evaluate the accuracy of the device measurement, water and 2-propanol are utilized as standard liquids, and their vapor pressure is measured with a maximum uncertainty of ∼1%. This apparatus can be replicated using inexpensive and commonly used laboratory fittings and fixtures, making it an indispensable tool for synthetic chemists and chemical engineers involved in the iterative synthesis of compounds, targeting different vapor–liquid equilibrium regimes.