Researchers over the past â¼200 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.
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.
Amino Acids , Camphor , Crystallography, X-Ray , Amino Acids/chemistry , Camphor/chemistry , Models, Molecular , Magnetic Resonance Spectroscopy
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.
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.
Peptides , Tyrosine , Tyrosine/chemistry , Peptides/chemistry , Phenylalanine/chemistry
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.
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.
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.
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.
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.
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.
Lactams , Lactones , Molecular Structure
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.
Carbon , Catalysis , Stereoisomerism
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.
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.
We report the efficient synthesis of cycloalkyl-fused naphthalenes through the [4 + 2]-cycloaddtion/decarboxylative aromatization of alkyne-tethered aryne insertion adducts. These scaffolds were difficult to synthesize using conventional reactions. The reaction proceeds via the formation of a benzopyrylium intermediate followed by intramolecular [4 + 2] cycloaddition and a subsequent decarboxylation pathway. This method is also compatible with allene-tethered substrates to afford similar products. In addition, the one-pot synthesis of polysubstituted naphthalenes via aryne insertion/benzannulation has also been developed in good yield.
A formal synthesis of (±)-cochlearol A was accomplished. The synthesis features Suzuki coupling and Friedel-Crafts cyclization as a convergent strategy to the functionalized tetralone ring and an intramolecular construction of the C/D ring involving sequential epoxide formation/acetal formation.
Acetals , Cyclization , Stereoisomerism , Terpenes
This Essay highlights the complex issue of twinning in science publications. Historical accounts present cases where two scientists focused on the same problem and came up with the same solution following different paths. This has changed in the present day. The concurrent publication of rather similar research papers from different groups has increased in frequency since 2010. In the past, twinning in research publications was serendipitous, and there was a healthy competition among teams working on similar projects. Today, twinning has become more frequent. This can be attributed to the urge of researchers to have publications on popular topics, the tendency to base research programs on popular keywords, and funding agencies preferentially supporting certain areas of research. With vast amounts of literature being generated, editorial offices and referees may not be able to find these twins very easily. As we inch away from human ingenuity towards artificial intelligence, twinning may become even more frequent.
A domino approach to bridged cycloocta[b]indolone through a cascade of aza-Piancatelli rearrangement/Friedel-Crafts alkylation is developed. This transformation has been realized by reaction of an indole-tethered 2-furylcarbinol and substituted aniline in the presence of a Lewis acid to initiate aza-Piancatelli rearrangement followed by an in situ intramolecular Friedel-Crafts alkylation to access bridged tetracyclic frameworks in one pot.
A serendipitous synthesis of N-substituted 2-amino-2'-hydroxy-1,1'-biaryls through an aryne annulation with indolyl ß-ketonitrile/ester in a cascade manner is demonstrated. The reaction sequence involves benzyne-mediated [2 + 2] Stoltz-type cycloaddition-cleavage and intramolecular Michael addition followed by C-N bond cleavage under transition-metal-free reaction conditions. Interestingly, while [4 + 2] Diels-Alder reaction is a possible pathway, no traces of the regioisomer was isolated.
Late-stage functionalization (LSF) aids drug discovery efforts by introducing functional groups onto C-H bonds on pre-existing skeletons. We adopted the LSF strategy to synthesize analogues of the abundantly available triterpenoid, glycyrrhetinic acid (GA), by introducing aryl groups in the A-ring, expanding the A-ring and selectively activating one methyl group of the gem-dimethyl groups. Intriguingly, two compounds were found to preferentially accumulate in the mitochondrial compartment of MDA-MB-231 breast cancer cells, to cause depolarization of mitochondrial membrane potential and to induce antiproliferative and anti-invasive effects through enhanced mitochondrial superoxide production with parallel depletion of GSH levels. Furthermore, intraperitoneal administration of these two compounds, in comparison with GA, greatly regressed breast tumor growth and metastasis in a SCID mouse model bearing labeled MDA-MB-231 cells.
Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Glycyrrhetinic Acid/pharmacology , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Female , Glycyrrhetinic Acid/analogs & derivatives , Glycyrrhetinic Acid/chemistry , Humans , Injections, Intraperitoneal , Mammary Neoplasms, Experimental/drug therapy , Mammary Neoplasms, Experimental/metabolism , Mammary Neoplasms, Experimental/pathology , Membrane Potential, Mitochondrial/drug effects , Mice , Mice, SCID , Mitochondria/drug effects , Mitochondria/metabolism , Superoxides/metabolism
A chiral-template-driven intramolecular Diels-Alder reaction has been used to build the tricyclic core of kalihinols, a group of antimalarial marine natural products. The key starting materials are commercially available nerol and sulcatone.
Biological Products , Cycloaddition Reaction , Molecular Structure
