Versatile Synthetic Methodologies Research Articles

Catalytic enantioselective reductive alkynylation of amides enables one-pot syntheses of pyrrolidine, piperidine and indolizidine alkaloids

The primary objective in synthetic organic chemistry is to develop highly efficient, selective, and versatile synthetic methodologies, which are essential for discovering new drug candidates and agrochemicals. In this study, we present a unified strategy for a one-pot, catalytic enantioselective synthesis of α-alkyl and α,α′-dialkyl pyrrolidine, piperidine, and indolizidine alkaloids using readily available amides and alkynes. This synthesis is enabled by the identification and development of an Ir/Cu/N-PINAP catalyzed highly enantioselective and chemoselective reductive alkynylation of α-unbranched aliphatic amides, which serves as the key reaction. This reaction is combined with Pd-catalyzed tandem reactions in a one-pot approach, enabling the collective, catalytic enantioselective total syntheses of eight alkaloids and an anticancer antipode with 90–98% ee. The methodology’s enantio-divergence is exemplified by the one-step access to either enantiomer of alkaloid bgugaine.

Unusual light-driven amplification through unexpected regioselective photogeneration of five-membered azaheterocyclic AIEgen.

Developing versatile synthetic methodologies with merits of simplicity, efficiency, and environment friendliness for five-membered heterocycles is of incredible importance to pharmaceutical and material science, as well as a huge challenge to synthetic chemistry. Herein, an unexpected regioselective photoreaction to construct a fused five-membered azaheterocycle with an aggregation-induced emission (AIE) characteristic is developed under mild conditions. The formation of the five-membered ring is both thermodynamically and kinetically favored, as justified by theoretical calculation and experimental evidence. Markedly, a light-driven amplification strategy is proposed and applied in selective mitochondria-targeted cancer cell recognition and fluorescent photopattern fabrication with improved resolution. The work not only delivers the first report on efficiently generating a fused five-membered azaheterocyclic AIE luminogen under mild conditions via photoreaction, but also offers deep insight into the essence of the photosynthesis of fused five-membered azaheterocyclic compounds.

Time Economy in Total Synthesis

It is often said that "time is money". This is certainly true in a multistep synthesis when a high-valued product or set of products is needed urgently. Fulfilling this need requires the sensible balancing of atom economy, step economy, and redox economy with the time taken to make the product. In this age of flu-based pandemics, the need for rapid provision of effective therapeutic agents makes the importance of "time economy" particularly clear. In this Perspective, the importance of time economy in total synthesis is described, as well as the general considerations underlining the timely production of desired molecules. As case studies, the syntheses of Tamiflu, Corey lactone, and ibuprofen are discussed, with emphasis on comparing classical and contemporary approaches to a rapid total synthesis. By using modern tactics such as one-pot reaction procedures and versatile synthetic methodologies such as organocatalyst mediated domino reactions coupled with strict-control technologies such as flow chemistry, Tamiflu and Corey lactone can now be synthesized within 60 and 152 min, respectively, using one vessel via a batch system. Tamiflu and ibuprofen can be prepared via flow system, and their total residence times are 11.5 and 3 min, respectively.

Cyclobutane-Containing Scaffolds as Useful Intermediates in the Stereoselective Synthesis of Suitable Candidates for Biomedical Purposes: Surfactants, Gelators and Metal Cation Ligands

Efficient and versatile synthetic methodologies are reported for the preparation of products that are suitable candidates to be used as surfactants, gelators for hydroxylic solvents or metal cation ligands, with potential use in several fields including biomedical applications. The common structural feature of all the synthesized products is the presence of a cis or trans-1,2- or cis-1,3-difunctionalized cyclobutane ring. In the two first cases, the key intermediates including enantiomerically pure 1,3-diamines and 1,3-amino alcohols have been prepared from β-amino acid derivatives obtained, in turn, from a chiral half-ester. This compound is also precursor of γ-amino esters. Furthermore, two kind of polydentate ligands have also been synthesized from a symmetric 1,5-diamine obtained from norpinic acid, which was easily prepared from commercial verbenone.

Synthesis and Antioxidant Activity of a New Class of Pyridinylcarbamoylmethyl Pyrrolyl/Pyrazolylcarboxamides

A new class of pyridinylcarbamoylmethyl pyrrolyl/pyrazolylcarboxamides was prepared from the synthetic intermediate pyridinylcarbamoylmethyl cinnamamide adopting simple and versatile synthetic methodologies. All the synthesized compounds were evaluated for antioxidant activity. Among all the tested compounds, the methoxy‐substituted pyrazolyl pyridines displayed significant antioxidant activity in all the three methods when compared with the standard ascorbic acid. Moreover, compounds having more number of electron‐donating groups exhibited greater activity.

Fighting Cancer with Corroles.

Corroles are exceptionally promising platforms for the development of agents for simultaneous cancer-targeting imaging and therapy. Depending on the element chelated by the corrole, these theranostic agents may be tuned primarily for diagnostic or therapeutic function. Versatile synthetic methodologies allow for the preparation of amphipolar derivatives, which form stable noncovalent conjugates with targeting biomolecules. These conjugates can be engineered for imaging and targeting as well as therapeutic function within one theranostic assembly. In this review, we begin with a brief outline of corrole chemistry that has been uniquely useful in designing corrole-based anticancer agents. Then we turn attention to the early literature regarding corrole anticancer activity, which commenced one year after the first scalable synthesis was reported (1999-2000). In 2001, a major advance was made with the introduction of negatively charged corroles, as these molecules, being amphipolar, form stable conjugates with many proteins. More recently, both cellular uptake and intracellular trafficking of metallocorroles have been documented in experimental investigations employing advanced optical spectroscopic as well as magnetic resonance imaging techniques. Key results from work on both cellular and animal models are reviewed, with emphasis on those that have shed new light on the mechanisms associated with anticancer activity. In closing, we predict a very bright future for corrole anticancer research, as it is experiencing exponential growth, taking full advantage of recently developed imaging and therapeutic modalities.

Designing Dendrimer and Miktoarm Polymer Based Multi-Tasking Nanocarriers for Efficient Medical Therapy.

To address current complex health problems, there has been an increasing demand for smart nanocarriers that could perform multiple complimentary biological tasks with high efficacy. This has provoked the design of tailor made nanocarriers, and the scientific community has made tremendous effort in meeting daunting challenges associated with synthetically articulating multiple functions into a single scaffold. Branched and hyper-branched macromolecular architectures have offered opportunities in enabling carriers with capabilities including location, delivery, imaging etc. Development of simple and versatile synthetic methodologies for these nanomaterials has been the key in diversifying macromolecule based medical therapy and treatment. This review highlights the advancement from conventional “only one function” to multifunctional nanomedicine. It is achieved by synthetic elaboration of multivalent platforms in miktoarm polymers and dendrimers by physical encapsulation, covalent linking and combinations thereof.

Erratum to: Synthesis and antioxidant activity of a new class of sulfone/sulfonamide-linked bis(oxadiazoles), bis(thiadiazoles), and bis(triazoles)

A new class of sulfone/sulfonamide-linked bis(oxadiazoles), bis(thiadiazoles), and bis(triazoles) were prepared from the synthetic intermediates sulfonyldiacetic acid, arylsulfonylacetic acid hydrazide, and arylaminosulfonylacetic acid hydrazide adopting simple and versatile synthetic methodologies. All the new compounds were tested for their antioxidant activity. Amongst all the tested compounds, methyl-substituted bis(oxadiazoles) (8b and 11b) were found to be potential antioxidant agents. It was also observed that sulfonamide-linked bis(oxadiazoles), bis(thiadiazoles), and bis(triazoles) showed comparatively higher antioxidant activity than sulfone-linked bis(oxadiazoles), bis(thiadiazoles), and bis(triazoles).

Synthesis and Antimicrobial Activity of Amido Sulfonamido Methane Linked Bisoxazoles, Bisthiazoles, and Bisimidazoles

A new class of amido sulfonamido methane linked bisoxazoles, bisthiazoles, and bisimidazoles were prepared adopting simple and versatile synthetic methodologies. The lead compounds were assayed for antimicrobial activity.

Synthesis and antioxidant activity of amido-linked benzoxazolyl/benzothiazolyl/benzimidazolyl-pyrroles and pyrazoles

The amido-linked benzoxazolyl/benzothiazolyl/benzimidazolyl-pyrroles and benzoxazolyl/benzothiazolyl/benzimidazolyl-pyrazoles were prepared from the synthetic intermediates (E)-N-(benzoxazol-2-yl)cinnamamide/(E)-N-(benzothiazol-2-yl)cinnamamide/(E)-N-(1H-benzimidazol-2-yl)cinnamamides adopting simple and versatile synthetic methodologies. All the new compounds were tested for antioxidant activity. The compounds 5b, 8b and 14b displayed greater antioxidant activity when compared with the standard drug ascorbic acid. It was also observed that benzoxazolyl amido-linked derivatives displayed greater radical scavenging activity than the benzothiazolyl and benzimidazolyl amido-linked derivatives. The amido-linked benzoxazolyl/benzothiazolyl/benzimidazolyl-pyrroles and benzoxazolyl/benzothiazolyl/benzimidazolyl-pyrazoles were prepared from the synthetic intermediates (E)-N-(benzoxazol-2-yl)cinnamamide/(E)-N-(benzothiazol-2-yl)cinnamamide/(E)-N-(1H-benzimidazol-2-yl)cinnamamides adopting simple and versatile synthetic methodologies. All the new compounds were tested for antioxidant activity. The compounds 5b, 8b and 14b displayed greater antioxidant activity when compared with the standard drug Ascorbic acid. It was also observed that benzoxazolyl amido-linked derivatives displayed greater radical scavenging activity than the benzothiazolyl and benzimidazolyl amido-linked derivatives.

Synthesis and Antioxidant Activity of Bis and Tris Heterocycles

A variety of bis heterocycles, oxazolyl/thiazolyl/imidazolyl oxadiazoles having a styryl sulfonylmethyl group at the 5-position of oxadiazole and tris heterocycles having a pyrrolyl/pyrazolyl sulfonylmethyl group at the 5-position of oxadiazole were prepared adopting simple and versatile synthetic methodologies. All the compounds were screened for their antioxidant activities. Compound 5b displayed radical scavenging activity in all the three methods greater than the standard ascorbic acid, whereas compounds 8b and 14b showed activities equal to the standard ascorbic acid.

Synthesis and Antimicrobial Activity of Azole Derivatives

A new class of mono and bis heterocycles, sulfonylmethaneamido linked oxazoles, thiazoles, imidazoles, pyrrolyl oxazoles, pyrrolyl thiazoles and pyrrolyl imidazoles were prepared adopting simple and versatile synthetic methodologies. The compound chloro substituted imidazolyl styrylsulfonylacetamide is the most potent antimicrobial agent particularly against Pseudomonas aeruginosa and Penicillium chrysogenum.

Organocatalytic Asymmetric Additions to meso‐Anhydrides and Azlactones

AbstractThis review charts the recent progress of two related, yet distinct organocatalytic processes: the desymmetrisation of meso‐anhydrides and the dynamic kinetic resolution of azlactones. Driven by recent advances in catalyst design, both these processes have undergone something of a renaissance in recent years and are now becoming very powerful and versatile synthetic methodologies. The material is presented in a critical fashion and the material is organised by reaction type and catalyst class.

Molecular and Supramolecular Architectures of Organic Semiconductors for Field‐Effect Transistor Devices and Sensors: A Synthetic Chemical Perspective

AbstractOrganic field‐effect transistors (OFETs) are key devices in organic electronics, and their performances largely depend on molecular structure and solid‐state organization of the π‐conjugated compounds used as semiconductors. This microreview reports several examples of materials for OFET devices and sensors, which have been selected to highlight the basic criteria of molecular design together with the synthetic logic driving the development of organic semiconductors. Versatile synthetic methodologies enable to optimize properties by tailoring molecular structures and functionalization, thus playing a key role in the progress of OFET technology, and more in general of organic electronics, which is emphasized in the discussion.

Phosphinopnictonium Cations: High Yield and General Preparative Procedures for New Interpnictogen Frameworks Exploiting As→P and Sb→P Coordinate Bonds

Reactions of R(3)Pn (Pn = As or Sb; R = Me, Et or Ph) with R'(2)PCl or R'PCl(2) (R' = Me, Et, Ph, Cy, (i)Pr), in the presence of a halide abstracting agent (Me(3)SiOSO(2)CF(3), GaCl(3), or AlCl(3)), give salts with cations containing Pn-P bonds. The bond formation is envisaged to proceed by activation of the P-Cl bond and coordination of the pnictine to the resulting phosphorus cation (R'(2)P(+) or R'P(2+), respectively). Salts of the first phosphinoarsonium cations, [R(3)As-PR'(2)](+), and the first 2-phosphino-1,3-diarsonium dications, [R(3)AsP(R')AsR(3)](2+), have been isolated and comprehensively characterized. In contrast, reactions involving Ph(3)Sb give 2,3-diphosphino-1,4-distibonium dications, [R(3)SbP(R')P(R')SbR(3)](2+), resulting from a single P-Cl activation (abstraction) at each of two phosphorus centers and reductive P-P coupling effected by Ph(3)Sb. The analogous 2,3-diphosphino-1,4-diarsonium dication [R(3)AsP(R')P(R')AsR(3)](2+) can be accessed from the 2,3-diphosphino-1,4-distibonium cation by a ligand exchange reaction, which also provides the phosphorus derivative 2,3-diphosphino-1,4-diphosphonium [R(3)PP(R')P(R')PR(3)](2+). The versatile synthetic methodologies toward the new P-As and P-Sb frameworks demonstrate the potential for diversification and systematic expansion of interpnictogen compounds.

Further Evidence for 2-Alkyl-2-carboxyazetidines as γ-Turn Inducers

Reverse turns, a common motif in proteins and peptides, have attracted attention due to their relevance in a wide variety of biological processes. In an attempt to artificially imitate and stabilize these turns in short peptides, we have developed versatile synthetic methodologies for the preparation of 2-alkyl-2-carboxyazetidines and incorporated them into the i + 1 position of model tetrapeptides, where they have shown a tendency to induce gamma-turns. However, to ascertain the general utility of these restricted amino acids as gamma-type reverse turn inducers, it was then required to study the conformational preferences when located at other positions. To this end, model tetrapeptides R-CO-Ala-Xaa-NHMe, containing differently substituted azetidine moieties (Xaa = Aze, 2-MeAze, 2-BnAze) at the i + 2 position, were synthesized and subjected to a thorough conformational analysis. The theoretical and experimental results obtained, including the X-ray diffraction structure of a dipeptide derivative containing this skeleton, provide evidence that the 2-alkyl-2-carboxyazetidine scaffold is able to efficiently induce gamma-turns when incorporated into these short peptides, irrespective of their localization in the peptide chain.

Expeditious Synthesis of 1,3,4-Trisubstituted Pyrazoles from Baylis-Hillman Adducts

The pyrazole nucleus is present in a wide variety of biologically interesting compounds, which exhibit antihyperglycemic, analgesic, anti-inflammatory, antipyretic, antibacterial, hypoglycemic, sedative-hypnotic activity. Thus, continuous efforts have been devoted to the development of more general and versatile synthetic methodologies to this class of compounds. Recently we have reported on the regio-selective synthesis of 1,3,4,5-tetrasubstituted pyrazole derivatives from the reaction of Baylis-Hillman adducts of alkyl vinyl ketone and hydrazine derivatives (Scheme 1). During the continuous studies on the chemical transformations of Baylis-Hillman adducts including the synthesis of pyrazoles we presumed that we could synthesize 1,3,4-trisubstituted pyrazoles from the reaction of hydrazine derivatives and acyloxiranes, which could be synthesized easily from Baylis-Hillman adducts (Scheme 2). According to the reported method, the required acyloxiranes 2a-e were synthesized in moderate yields from the corresponding Baylis-Hillman adducts 1 by NaOCl in the presence of silica gel in acetonitrile. With these acyloxiranes 2a-e in our hands, we examined the synthesis of corresponding pyrazoles under a variety of conditions, and we found that the reaction of 2a-e and various hydrazine hydrochlorides in 1,2-dichloroethane at refluxing temperature afforded the best results. As shown in Table 1, the reaction of 2a with phenylhydrazine hydrochloride, tertbutylhydrazine hydrochloride, 2,4-difluorophenylhydrazine hydrochloride afforded 3a-c in moderate yields (39-75%). In the reaction of 2,4-dinitrophenylhydrazine (entry 4), we used p-toluenesulfonic acid as the acid catalyst. Other acyloxiranes 2b-e showed similar results in the reactions of phenylhydrazine hydrochloride (36-71%, entries 5-8). Although we isolated the products in moderate yields in most cases, however, the yields of 3b and 3f were relatively low due to the formation of many intractable side products. In summary, we disclosed an expeditious synthesis of 1,3,4-trisubstituted pyrazoles from the reaction of hydrazine derivatives and the acyloxiranes, which were prepared from Baylis-Hillman adducts.

Toggling Enantioselective Catalysis — A Promising Paradigm in the Development of More Efficient and Versatile Enantioselective Synthetic Methodologies

AbstractFor Abstract see ChemInform Abstract in Full Text.

Toggling enantioselective catalysis--a promising paradigm in the development of more efficient and versatile enantioselective synthetic methodologies.

The increasingly needed synthesis of both enantiomers of a chiral compound usually requires the use of both enantiomers of a chiral catalyst. Several of the usually employed chiral ligands are naturally available in only one enantiomeric form, the antipode often being of labor-intensive preparation. Enantiodivergent asymmetric catalysis has accrued in importance in this regard, in that it allows expeditious access to both enantiomers of a product without any direct modification on the chemical structure of the chiral promoter. Various promising examples will be discussed throughout the review. If available or envisageable, a mechanistic rationale for the observed enantioinversion will be outlined.