Synthetic Opportunities Research Articles

Adoption of green methodology in industry for the synthesis of Sildenafil citrate & Celecoxib: A case study

Medicines are the imperative constituent in the present day lifestyle and their consumption for different cause’s increases day by day. Synthesis of most of the drugs involves use of toxic chemicals and hazardous solvents, tedious workup or lengthy strategies. The needs of environment friendly procedures are the prerequisites of current environment concern. The known drug candidates Sildenafil citrate and Celecoxib are selected for the investigation and study for improved synthetic opportunities. It is found that several alterations are useful in the synthesis of these biological active profiles and they are adopted for large scale production of the compound in pharmaceutical industries. The old and new synthetic strategies are discussed in this case study based article.

Acetylene and Ethylene: Universal C2 Molecular Units in Cycloaddition Reactions

AbstractAcetylene and ethylene are the smallest molecules that contain an unsaturated carbon–carbon bond and can be efficiently utilized in a large variety of cycloaddition reactions. In this review, we summarize the application of these C2 molecular units in cycloaddition chemistry and highlight their amazing synthetic opportunities.1 Introduction2 Fundamental Features and Differences of Cycloaddition Reactions Involving Acetylene and Ethylene3 (2+1) Cycloaddition4 [2+2] Cycloaddition5 (3+2) Cycloaddition6 [4+2] Cycloaddition7 (2+2+1) Cycloaddition8 [2+2+2] Cycloaddition9 The Use of Acetylene and Ethylene Cycloaddition for Deuterium and 13C Labeling10 Conclusions

Inside Cover: Synthetic Molecular Photoelectrochemistry: New Frontiers in Synthetic Applications, Mechanistic Insights and Scalability (Angew. Chem. Int. Ed. 12/2022)

Molecular photoelectrochemistry, choose your catalysis: Molecular photoelectrochemistry, allowing access to a broader window of single electron transfer chemistry in a greener way, is a rapidly expanding toolbox for synthesis and selective functionalizations of complex molecules. In their Review (DOI: 10.1002/anie.202107811), Joshua Barham et al. capture exciting synthetic opportunities, key mechanistic insights and evolving batch and flow reactor platforms allowing screening and scalability of reactions.

A bifunctional nanozyme of carbon dots-mediated Co9S8 formation

Controlling the size of nanocrystals and inhibiting their agglomeration are of paramount importance for achieving ideal catalytic performance. Here we discovered that carbon dots (CDs) are not only able to serve as reductants but also as stabilizers of ultrasmall Co9S8 nanocrystals by means of their surface terminal groups. As a result, ultrasmall Co9S8 nanocrystals are incorporated into porous carbon nanosheets formed by splicing CDs. The resultant nanocomposites display a rich pore structure accompanying with large specific surface area and outstanding bifunctional performances to mimic the catalytic activity of peroxidase and oxidase without exerting any external energy. More importantly, the unique architecture endows Co9S8 nanocrystals with high stability and good durability. The nanocomposites have been demonstrated as a colorimetric sensor for detection of ascorbic acid with a superior anti-interference ability as well as a detection limit of 0.2 μM. Our findings open new synthetic opportunities by tuning the interaction of CDs with the surrounding environment and enable advanced applications such as biomedicine and catalytic transformations.

A Family of Externally-Functionalised Coordination Cages

New synthetic routes are presented to derivatives of a (known) M8L12 cubic coordination cage in which a range of different substituents are attached at the C4 position of the pyridyl rings at either end of the bis(pyrazolyl-pyridine) bridging ligands. The substituents are (i) –CN groups (new ligand LCN), (ii) –CH2OCH2–CCH (containing a terminal alkyne) groups (new ligand LCC); and (iii) –(CH2OCH2)3CH2OMe (tri-ethyleneglycol monomethyl ether) groups (new ligand LPEG). The resulting functionalised ligands combine with M2+ ions (particularly Co2+, Ni2+, Cd2+) to give isostructural [M8L12]16+ cage cores bearing 24 external functional groups; the cages based on LCN (with M2+ = Cd2+) and LCC (with M2+ = Ni2+) have been crystallographically characterised. The value of these is twofold: (i) exterior nitrile or alkene substituents can provide a basis for further synthetic opportunities via ‘Click’ reactions allowing in principle a diverse range of functionalisation of the cage exterior surface; (ii) the exterior –(CH2OCH2)3CH2OMe groups substantially increase cage solubility in both water and in organic solvents, allowing binding constants of cavity-binding guests to be measured under an increased range of conditions.

E3 Ligase Ligands in Successful PROTACs: An Overview of Syntheses and Linker Attachment Points.

Proteolysis-targeting chimeras (PROTACs) have received tremendous attention as a new and exciting class of therapeutic agents that promise to significantly impact drug discovery. These bifunctional molecules consist of a target binding unit, a linker, and an E3 ligase binding moiety. The chemically-induced formation of ternary complexes leads to ubiquitination and proteasomal degradation of target proteins. Among the plethora of E3 ligases, only a few have been utilized for the novel PROTAC technology. However, extensive knowledge on the preparation of E3 ligands and their utilization for PROTACs has already been acquired. This review provides an in-depth analysis of synthetic entries to functionalized ligands for the most relevant E3 ligase ligands, i.e. CRBN, VHL, IAP, and MDM2. Less commonly used E3 ligase and their ligands are also presented. We compare different preparative routes to E3 ligands with respect to feasibility and productivity. A particular focus was set on the chemistry of the linker attachment by discussing the synthetic opportunities to connect the E3 ligand at an appropriate exit vector with a linker to assemble the final PROTAC. This comprehensive review includes many facets involved in the synthesis of such complex molecules and is expected to serve as a compendium to support future synthetic attempts towards PROTACs.

Enantioselective Heck-Matsuda Reactions: From Curiosity to a Game-Changing Methodology.

The enantioselective palladium-catalyzed Heck arylation of olefins using arenediazonium salts is one of the last features in the evolution of a synthetic method known as the Heck-Matsuda reaction. This personal account highlights the development of the enantioselective Heck-Matsuda reaction in its initial stages, the challenges faced along the way, and the interesting findings that opened new synthetic opportunities, mainly from our laboratory, featuring the Heck-Matsuda reaction as a central player in the synthesis of bioactive and functional molecules.

Synthetic Opportunities and Challenges for Macrocyclic Kinase Inhibitors.

Macrocycles are typically cyclic variants of inhibitors derived from uncyclized canonical molecules or from natural products. For medicinal chemistry, drug-like macrocycles have received increasing interest over the past few years, since it has been demonstrated that macrocyclization can favorably alter the biological and physiochemical properties as well as selectivity in comparison to the acyclic analogue. Recent drug approvals such as Lorlatinib, glecaprevir, or voxilaprevir underline the clinical relevance of drug-like macrocycles. However, the synthesis of drug-like macrocycles can be challenging, since the ring-closing reaction is generally challenging with yields depending on the size and geometry of the bridging linker. Nevertheless, macrocycles are one opportunity to expand the synthetic toolbox for medicinal chemistry to provide bioactive molecules. Therefore, we reviewed the past literature of drug-like macrocycles highlighting reactions that have been successfully used for the macrocyclization. We classified the cyclization reactions by their type, ring-size, yield, and macrocyclization efficiency index.

Chemistry of oxaphosphirane complexes

Abstract In this review, the chemistry of σ3λ3-oxaphosphirane metal complexes is presented which was developed over the last 30 years. Important aspects like the improvements in the synthetic accessibility, starting from epoxidation of phosphaalkene complexes in the early 90s to the usage of Li/Cl phosphinidenoid complexes in formal [2+1] cycloaddition reactions with aldehydes and ketones are discussed. Furthermore, physical properties, depending on the P-substituent and metal fragment, as well as the results of quantum chemical calculations are presented, with a special focus on the ring strain energy. The existence of three different polar bonds in the oxaphosphirane ligand open a great variety of synthetic opportunities such as the use of these metal complexes in ring rearrangements, ring expansions catalyzed by strong Bronsted acids, ring opening reactions with protic substrates giving access to 1,2-difunctional phosphane complexes or “ring deconstruction” with different nucleophiles.

Challenges and Opportunities in the Post‐Synthetic Modification of Interlocked Molecules

AbstractSeveral strategies have been successfully utilised to obtain a wide range of interlocked molecules. However, some interlocked compounds are still not obtained directly and/or efficiently from non‐interlocked components because the requisites for self‐assembly cannot always be enforced. To circumvent such a synthetic problem, a strategy that consists of synthesizing an isolable and storable interlocked building block in a step that precedes its modification is an appealing chemical route to more sophisticated interlocked molecules. Synthetic opportunities and challenges are closely linked to the fact that the mechanical bond might greatly affect the reactivity of a functionality of the encircled axle, but that the interlocked architecture needs to be preserved during the synthesis. Hence, the mechanical bond plays a fundamental role in the strategy employed. This Review focuses on the challenging post‐synthetic modifications of interlocked molecules, sometimes through cleavage of the axle's main chain, but always with conservation of the mechanical bond.

Challenges and Opportunities in the Post-Synthetic Modification of Interlocked Molecules.

Several strategies have been successfully utilised to obtain a wide range of interlocked molecules. However, some interlocked compounds are still not obtained directly and/or efficiently from non-interlocked components because the requisites for self-assembly cannot always be enforced. To circumvent such a synthetic problem, a strategy that consists of synthesizing an isolable and storable interlocked building block in a step that precedes its modification is an appealing chemical route to more sophisticated interlocked molecules. Synthetic opportunities and challenges are closely linked to the fact that the mechanical bond might greatly affect the reactivity of a functionality of the encircled axle, but that the interlocked architecture needs to be preserved during the synthesis. Hence, the mechanical bond plays a fundamental role in the strategy employed. This Review focuses on the challenging post-synthetic modifications of interlocked molecules, sometimes through cleavage of the axle's main chain, but always with conservation of the mechanical bond.

Functionalized Tetrazole Energetics: A Route to Enhanced Performance

AbstractTetrazoles are a class of heterocyclic compounds. Many tetrazole derivatives have been studied extensively as potential high energy materials. Compared with other nitrogen‐rich heterocycles, most tetrazole‐based heterocycles demonstrate superior properties due to the higher density and heat of formation levels. A large variety of advanced energetic materials have been achieved based on the combination of tetrazole moieties with a collection of bridges. This review is an overview of the recent developments of energetic tetrazole structures, and where possible, information such as the synthetic methods, and physical and detonation properties are provided. Given the synthetic opportunities and outstanding properties, energetic materials based on tetrazole structures are undoubtedly promising candidates for the development of highly energetic materials for civilian or military applications.

Recent strategies used in the synthesis of saturated four-membered heterocycles.

The importance and prevalance of O-, N-, and S-atom containing saturated four-membered ring motifs in biologically active molecules and potential therapeutics continues to drive efforts in their efficient synthetic preparation. In this review, general and recent strategies for the synthesis of these heterocycles are presented. Due to the limited potential bond disconnections, retrosynthetic strategies are broadly limited to cyclizations and cycloadditions. Nonetheless, diverse approaches for accessing cyclization precursors have been developed, ranging from nucleophilic substitution to C-H functionalization. Innovative methods for substrate activation have been developed for cycloadditions under photochemical and thermal conditions. Advances in accessing oxetanes, azetidines, and thietanes remain active areas of research with continued breakthroughs anticipated to enable future applications.

Catalytic access to carbocation intermediates via nitrenoid transfer leading to allylic lactams

Carbocation intermediacy is postulated in numerous organic transformations and provides the foundation for retrosynthetic logics in chemical synthesis. Although a number of catalytic approaches are designed to generate transient carbocations under mild conditions, there is room for improvement in the context of selectivity control and synthetic utility. Here we present an approach that enables catalytic access to carbocation intermediates via metal-nitrenoid transfer into alkenes, which subsequently allows a regiocontrolled elimination reaction. Customized catalysts are capable of bypassing competing pathways of the reactive intermediates to furnish valuable allylic lactams with excellent regioselectivity. Mechanistic investigations suggest that the ligand plays a critical role as an internal base in the selectivity-determining proton transfer process. This protocol is broadly applicable for preparing both five- and the more challenging four-membered allylamides. The virtue of this platform is further demonstrated by achieving the enantioselective construction of γ-lactams. The reactivity of transient carbocations provides interesting synthetic opportunities, but the selectivity control is challenging. Now, catalytic access to carbocation intermediates via metal-nitrenoid transfer into alkenes is reported and their regiocontrolled elimination is achieved, allowing the production of allylic lactams.

Asymmetric Catalytic Reactions of Donor–Acceptor Cyclopropanes

AbstractDue to the synergistic “push–pull” effect of vicinal electron‐donating and electron‐withdrawing groups, donor–acceptor (D‐A) cyclopropanes have been recognized as one of the most powerful building blocks to generate polyfunctional reactive intermediates after a strain‐driven ring cleavage. Enantioselective reactions of D‐A cyclopropanes provide an efficient approach to enantioenriched acyclic and cyclic compounds. A number of chiral Lewis/Brønsted acids, transition metals, and organocatalysts have been designed for such transformations, including ring‐openings, annulations, and rearrangements. This minireview highlights the developments and new advances in this field and describes new synthetic opportunities offered by these interesting methodologies.

Asymmetric Catalytic Reactions of Donor-Acceptor Cyclopropanes.

Due to the synergistic "push-pull" effect of vicinal electron-donating and electron-withdrawing groups, donor-acceptor (D-A) cyclopropanes have been recognized as one of the most powerful building blocks to generate polyfunctional reactive intermediates after a strain-driven ring cleavage. Enantioselective reactions of D-A cyclopropanes provide an efficient approach to enantioenriched acyclic and cyclic compounds. A number of chiral Lewis/Brønsted acids, transition metals, and organocatalysts have been designed for such transformations, including ring-openings, annulations, and rearrangements. This minireview highlights the developments and new advances in this field and describes new synthetic opportunities offered by these interesting methodologies.

Azetidines and their applications in asymmetric catalysis

Abstract Since the early 1990s asymmetric catalytic applications of chiral, azetidine-derived, ligands and organocatalysts have been developed and utilised to engender asymmetry in reactions including Friedel-Crafts alkylations, Henry reactions and Michael-type reactions. This review surveys the effective synthetic opportunities presented by chiral azetidines in asymmetric catalysis. In order to benchmark, contrast and evaluate these asymmetric azetidine-containing catalysts, comparisons with aziridine- and pyrrolidine-containing analogues are drawn.

N,N-Diacylaminals as Emerging Tools in Synthesis: From Peptidomimetics to Asymmetric Catalysis.

N,N-Diacylaminals are flexible molecular scaffolds that have commonly been utilized as amide surrogates in peptidomimetics. The singularities of this motif as an N-acyl imine equivalent and as hydrogen-bond donor have recently opened new synthetic opportunities, especially in the field of asymmetric catalysis. This concept article highlights this diverse synthetic potential and provides the elements necessary for further developments.

Recent Advances in Applying Carbonyl‐stabilized Phosphorus Ylides for Catalysis

AbstractThe exploration of new catalytic properties of the known functionalities would facilitate the exploitation of new ligands and/or organocatalysts that are able to achieve reactivity and selectivity unattainable by known ones. In this context, carbonyl‐stabilized phosphorus ylides have emerged as a type of novel ligand motifs and organocatalysts, exhibiting versatile catalytic activity towards some important organic reactions such as cross‐couplings, cyanation, CO2 fixation. This Minireview summarizes these recent advances, highlights the advantages and limitations, and outlines synthetic opportunities still open for further investigation.

Biomolecular Densely Grafted Brush Polymers: Oligonucleotides, Oligosaccharides and Oligopeptides.

In this Minireview, we describe synthetic polymers densely functionalized with sequence-defined biomolecular sidechains. We focus on synthetic brush polymers of oligonucleotides, oligosaccharides, and oligopeptides, prepared via graft-through polymerization from biomolecule functionalized monomers. The resulting structures are brush polymers wherein a biomolecular graft is positioned at each monomer backbone unit. We describe key synthetic milestones, identify synthetic opportunities, and highlight recent advances in the field, including biological applications.