Stereo flexible synthesis of the C8-C23 fragment of antarlides, androgen receptor antagonists.

A practical and efficient synthesis of the C8-C23 fragment of antarlides A-H, incorporating six stereocenters and a conjugated diene, is reported. A strategic combination of synthetic methods, including CBS reduction, Evans' aldol reaction, Keck-Maruoka allylation, and enzymatic resolution, enabled the selective introduction of these stereocenters. Furthermore, the pivotal coupling of key fragments is successfully executed through a Julia-Kocienski olefination reaction, connecting the C8-C14 and C15-C23 subunits.

Practical Access to Fused Carbazoles via Oxidative Benzannulation and their Photophysical Properties.

An aryne annulation strategy for the synthesis of fused carbazoles is developed using indolyl ß-ketonitrile in a cascade manner. The reaction sequence involves aryne-mediated [2 + 2] cycloaddition cleavage and intramolecular Michael addition, followed by oxidation under transition-metal-free reaction conditions. Subsequently, conversion of benzo[b]carbazole-6-carbonitrile to carbazole quinone is observed upon prolongation of the reaction time. Furthermore, these materials exhibit high quantum efficiency, which promotes the light-emitting diode applications.

Path toward "Net Zero Organic Synthesis".

Researchers over the past ∼200 years have accomplished the synthesis of simple to very complex molecules; however, the concept of ideal synthesis has still not reached maturity. Of late, the "Net Zero" concept has captured the imagination of many fields of technology, in tune with Ideal Synthesis. The current Viewpoint covers the principles of ideal synthesis being discussed in the literature and how one could take up the synthesis of organic molecules considering the Net Zero concept to make this central science well-accepted by critics of this important field.

6-Strand to Stable 10/12 Helix Conformational Switch by Incorporating Flexible ß-hGly in the Homooligomers of Camphor Derived ß-Amino Acid: NMR and X-Ray Crystallographic Evidence.

Rational design of unnatural amino acid building blocks capable of stabilizing predictable secondary structures similar to protein fragments is pivotal for foldamer chemistry/catalysis. Here, we introduce novel ß-amino acid building blocks: [1S,2R,4R]exoCDA and [1S,2S,4R]endoCDA, derived from the abundantly available R(+)-camphor, which is traditionally known for its medicinal value. Further, we demonstrate that the homooligomers of exoCDA adopt 6-strand conformation, which switches to a robust 10/12-helix simply by inserting flexible ß-hGly spacer at alternate positions (1 : 1 ß-hGly/exoCDA heterooligomers), as evident by DFT-calculations, solution-state NMR spectroscopy and X-ray crystallography. To the best of our knowledge, this is the first example of crystalline-state structure of left-handed 10/12-mixed helix, that is free from the conventional approach of employing ß-amino acids of either alternate chirality or alternate ß2/ß3 substitutions, to access the 10/12-helix. The results also show that the homooligomers of heterochiral exoCDA don't adopt helical fold, instead exhibit banana-shaped strands, whereas the homodimers of the other diastereomer endoCDA, nucleate 8-membered turns. Furthermore, the homo-exoCDA and hetero-[ß-hGly-exoCDA] oligomers are found to exhibit self-association properties with distinct morphological features. Overall, the results offer new possibilties of constructing discrete stable secondary and tertiary structures based on CDAs, which can accommodate flexible residues with desired side-chain substitutions.

Metal-free functionalization of tyrosine residues in short peptides and study of the morphological alterations.

An efficient functionalization of tyrosine residues in phenolic regions is achieved under metal-free conditions. The strategy involves the conversion of a tyrosine residue to 4-amino phenylalanine or 4-amino-3-methoxy phenylalanine in short peptides through a controlled oxidative dearomatization. This transformation is achieved in one pot with good yields and excellent regioselectivity. Consequently, the self-assembly of the peptide compounds has been studied at the nanoscopic level before and after functionalization. The results suggest that the peptide derivatives comprising amide groups promote intermolecular H-bonding interactions and the difference in -OH and -NH2 functional groups is found to be responsible for the morphological changes. Morphological transitions from 1D nanowires to 2D nanosheets were observed during functional group modification.

Synthesis of cis-fused cyclopentenone-pyrrolidine scaffolds via sequential aza-Piancatelli and Conia-ene type reactions in one pot.

A novel one-pot protocol that enables sequential execution of an aza-Piancatelli rearrangement and a Conia-ene type reaction has been developed under Lewis acid catalysis. Here, a combination of B(C6F5)3 and Cu(OTf)2, triethylamine, and triphenylphosphine yielded a wide range of cis-fused cyclopentenone-pyrrolidine scaffolds in one pot with good yields and diastereoselectivity.

SOLVENTS: From Past to Present.

Technological advancements in organic chemistry cannot be imagined without solvents, an essential evil due to well-recognized safety, health, and environmental risks and yet an integral part of the value chain for almost all industrially manufactured products intended for human use. A solvent serves as an essential liquid medium for different molecules to interact and react, generating products totally different from the original reactants. Reminiscences reveal water to be the first solvent used in the art of organic chemistry. This Viewpoint attempts to capture anecdotal theories and evidence on the use of this "magic liquid" and the progressive adoption of alternative liquid solvents, which have played a pivotal role in the evolution of synthetic organic chemistry. Synthetic organic chemistry, in turn, has sought to compete with nature in mimicking complex natural product syntheses in the laboratory on miniscule time scales compared with millions of years of evolutionary processes.

Therapeutic Potential of Benzimidazoisoquinoline Derivatives in Alleviating Murine Hepatic Fibrosis.

Short Title: Benzimidazoisoquinoline derivatives as potent antifibrotics Hepatic fibrosis is a pathological condition of liver disease with an increasing number of cases worldwide. Therapeutic strategies are warranted to target the activated hepatic stellate cells (HSCs), the collagen-producing cells, an effective strategy for controlling the disease progression. Benzimidazoisoquinoline derivatives were synthesized as hybrid molecules by the combination of benzimidazoles and isoquinolines to evaluate their anti-fibrotic potential using an in-vitro and in-vivo model of hepatic fibrosis. A small library of benzimidazoisoquinoline derivatives (1-17 and 18-21) was synthesized from 2-aryl benzimidazole and acetylene functionalities through C-H and N-H activation. Compounds (10 and its recently synthesized derivatives 18-21) depicted a significant decrease in PDGF-BB and/or TGFß-induced proliferation (1.7-1.9 -fold), migration (3.5-5.0 -fold), and fibrosis-related gene expressions in HSCs. These compounds could revert the hepatic damage caused by chronic exposure to hepatotoxicants, ethanol, and/or carbon tetrachloride as evident from the histological, biochemical, and molecular analysis. Anti-fibrotic effect of the compounds was supported by the decrease in the malondialdehyde level, collagen deposition, and gene expression levels of fibrosis-related markers such as α-SMA, COL1α1, PDGFRß, and TGFRIIß in the preclinical models of hepatic fibrosis. In conclusion, the synthesized benzimidazoisoquinoline derivatives (compounds 18, 19, 20, and 21) possess anti-fibrotic therapeutic potential against liver fibrosis.

Easy Access to Phenanthridinones via Metal-Free Cascade Benzannulation and C-N Bond Formation.

A concise route for the synthesis of dihydrobenzo[j]phenanthridinones has been disclosed through an aryne annulation strategy under metal-free reaction conditions. The reaction involves multiple C-C and C-N bond cleavages/formations via Diels-Alder reaction, aromatization-driven C-N bond cleavage, and amide formation.

Construction of Octahydro-4H-cyclopenta[b]pyridin-6-one Skeletons using Pot, Atom, and Step Economy (PASE) Synthesis.

Cascade aza-Piancatelli reaction and [3+3]/[4+2] cycloaddition reactions are carried out using the ideality principles of pot, atom, and step economy (PASE) synthesis. The reaction resulted in generation of octahydro-4H-cyclopenta[b]pyridin-6-one scaffolds. Moreover, octahydro-5,7a-epoxycyclopenta[cd]isoindol-4-one frameworks of gracilamine alkaloid and a novel decahydro-1H-dicyclopenta[cd,hi]isoindol-6-one were also realized in good yields with excellent regio- and diastereo-selectivities.

Design principles and functional basis of enantioselectivity of alanyl-tRNA synthetase and a chiral proofreader during protein biosynthesis.

Homochirality of the cellular proteome is attributed to the L-chiral bias of the translation apparatus. The chiral specificity of enzymes was elegantly explained using the 'four-location' model by Koshland two decades ago. In accordance with the model, it was envisaged and noted that some aminoacyl-tRNA synthetases (aaRS) that charge larger amino acids are porous to D-amino acids. However, a recent study showed that alanyl-tRNA synthetase (AlaRS) can mischarge D-alanine and that its editing domain, but not the universally present D-aminoacyl-tRNA deacylase (DTD), is responsible for correcting the chirality-based error. Here, using in vitro and in vivo data coupled with structural analysis, we show that AlaRS catalytic site is a strict D-chiral rejection system and therefore does not activate D-alanine. It obviates the need for AlaRS editing domain to be active against D-Ala-tRNAAla and we show that it is indeed the case as it only corrects L-serine and glycine mischarging. We further provide direct biochemical evidence showing activity of DTD on smaller D-aa-tRNAs that corroborates with the L-chiral rejection mode of action proposed earlier. Overall, while removing anomalies in the fundamental recognition mechanisms, the current study further substantiates how chiral fidelity is perpetuated during protein biosynthesis.

Substitution controlled aryne insertion: synthesis of diarylmethane/chromones.

Aryne insertion reaction with 2-aroyl malonates/cyanoesters lead to the formation of diarylmethane or chromones depending on the substitution on the aryne ring. The presence of an electronegative atom at the ortho position of arynes generates chromones, whereas other arynes lead to the formation of diarylmethanes, via a cascade double aryne insertion.

Rhodium catalysed intramolecular benzannulation for the formation of tetracyclic carbazoles.

Rhodium catalyzed alkyne-tethered intramolecular annulation has been demonstrated for the synthesis of tetracyclic carbazole skeletons and a series of five to eight-membered pyrido[3,2,1-jk]carbazoles were successfully obtained. The present atom economical annulation proceeded under mild reaction conditions, offering a broad substrate scope.

Total synthesis of antiviral drug, nirmatrelvir (PF-07321332).

The emergence and rapid spread of coronavirus disease 2019 (COVID-19), a potentially fatal disease, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has swiftly led to public health crisis worldwide. Hence vaccines and antiviral therapeutics are an important part of the healthcare response to combat the ongoing threat by COVID-19. Here, we report an efficient synthesis of nirmatrelvir (PF-07321332), an orally active SARS-CoV-2 main protease inhibitor.

Access to Spiroindanolactones/lactams through an Aryne Insertion/Spirocyclization Strategy.

An efficient and metal-free strategy for the synthesis of spiro-fused indanolactones/lactams has been developed for the reaction of arynes with α-chloroacetyl lactones/lactams. This strategy provides access to spiroindanone derivatives via aryne insertion/spirocyclization.

Organophotoredox-catalyzed cyanoalkylation of 1,4-quinones.

A visible-light-induced metal-free cyanoalkylation of 1,4-quinones under mild and redox-neutral conditions is described. This reaction proceeds at room temperature without the need of extra base or additive and is suitable for a variety of 1,4-quinones and differently substituted cyclobutanone oxime esters. Further transformation of cyano functionality to tetrazole and amine has also been demonstrated to showcase the advantage of this method to prepare drug-like molecules.

Continuous flow process for preparing budesonide.

Budesonide, a glucocorticosteroid, is used as anti-asthmatic drug that became generic in 2019. Existing preparation methods of budesonide require utilization of corrosive acids and involve expensive purification process. Thus, a new cost-effective continuous flow process for the synthesis of budesonide which belongs to the class of 16,17 acetals of pregnane core, is discussed in the present research findings. Flow reactor parameters such as flow rate, temperature, residence time, solution volumes, anti-solvents and reactor frequency are subjected to investigation on the preparation of molar ratio of budesonide epimers. Further, the suitable parameters entail for obtaining the desired molar ratio of epimers. In another aspect, particle size optimization studies are also performed to get the desired budesonide solid product. A continuous flow process for preparation of budesonide is identified from the present research investigation which can be readily transferred to industrial scale up.

Quaternary carbon construction through Piancatelli rearrangement: easy access to spirocyclopentenones.

A new and efficient approach to a series of novel multifunctionalized spirocyclopentenone scaffolds through Piancatelli rearrangement was developed under metal-free conditions. This method has been successfully applied to O-, N- and C-nucleophiles with excellent yields.

Cascade aryne insertion/vinylogous aldol reaction of vinyl-substituted ß-keto/enol carbonyls.

Cyclic and acyclic vinyl substituted ß-keto/enol carbonyl substrates, on reaction with arynes, result in differentially substituted naphthyl carbocycles, hitherto difficult to synthesize with existing protocols. While the substitutions on the arynes have no role, the ring size of the cyclic ß-keto/enol esters has a profound influence on the product formation.

Total synthesis of remdesivir.

Remdesivir, the first drug approved by the FDA to treat COVID-19, is in high demand for patients infected with the SARS-CoV-2 virus. Herein, we report a facile approach minimizing the protecting group manipulations to afford remdesivir in good overall yield.